WO2018050815A1 - Amide derivatives of squalamine for the treatment of infections - Google Patents

Amide derivatives of squalamine for the treatment of infections Download PDF

Info

Publication number
WO2018050815A1
WO2018050815A1 PCT/EP2017/073267 EP2017073267W WO2018050815A1 WO 2018050815 A1 WO2018050815 A1 WO 2018050815A1 EP 2017073267 W EP2017073267 W EP 2017073267W WO 2018050815 A1 WO2018050815 A1 WO 2018050815A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
isopropyl
formula
compounds
chenodeoxycholamide
Prior art date
Application number
PCT/EP2017/073267
Other languages
French (fr)
Inventor
Jean-Michel Brunel
Marine BLANCHET
Jean-Pascal MARC
Original Assignee
Virbac
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virbac filed Critical Virbac
Priority to EP17764847.4A priority Critical patent/EP3512864B1/en
Priority to US16/333,484 priority patent/US10780101B2/en
Priority to CN201780057107.1A priority patent/CN109996804B/en
Publication of WO2018050815A1 publication Critical patent/WO2018050815A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention relates to squalamine analogs for use in the treatment of bacterial, fungal, viral or parasitic infections in humans or animals, as well as pharmaceutical or veterinary compositions comprising them.
  • squalamine a natural steroid, mostly isolated from the tissues of a small shark Squalus acanthias, was found to be a very active substance with essentially anti-angiogenic activity against cells and anti-viral and antibacterial activity.
  • squalamine is an original molecule with an amphiphilic character. It thus comprises an apolar central portion (a cholestane-type skeleton) and two polar ends (a polyamine chain and a sulfate group).
  • this water-soluble polyaminosterol had generated interest in its antiangiogenic and antimicrobial properties on a variety of Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, fungi (Candia albicans, Candida). tropicalis) and protozoa.
  • Antibacterial aminosteroid derivatives of the polyamino cholestane or cholestene type are especially known for topical application locally, for the fast cutaneous-mucous decolonization of Staphylococcus aureus, especially in the form of ointment or cream.
  • These compounds have an interesting activity for preventing and / or inhibiting and / or treating bacterial, fungal, viral or parasitic infections in humans or animals.
  • These compounds are also compounds of choice as antibiotic substitutes.
  • domestic mammals such as ruminants, horses, pigs, dogs and cats and wild animals.
  • domestic mammals such as ruminants, horses, pigs, dogs and cats and wild animals.
  • pets more specifically for dogs and cats, or even rodents, and is more particularly for dogs and cats.
  • the compounds according to the invention allow an excellent activity against bacteria, while avoiding the appearance of resistance, which is a major advantage as the problem of the appearance of resistance to conventional antibiotics has become a public health problem. By their mechanism of action, different from that of antibiotics, the compounds of the invention are therefore excellent as alternatives to antibiotics.
  • the present invention relates to a compound of formula
  • R1 and R2 independently represent a hydrogen atom, a group
  • R ' represents a group - (CRaRb) nX- (CRcRd) m- [Y- (CReRf) o] t -NR9Rio, Pa, Rb, Rc, Pd, Pe and Rf independently represent a hydrogen atom, a (Ci-Cs) alkyl group or a (C 6 -Cio) aryl group,
  • X and Y independently represent a group -NR1 1-, a group -O- or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members,
  • R 1 represents a hydrogen atom, a (C 1 -C 5) alkyl group or a - (CH 2 ) S -NH 2 group ,
  • RI 5 and RI 6 independently represent a hydrogen atom, a (C 1 -C 5) alkyl group or a (C 6 -C 10) aryl group,
  • n, m, o and s independently represent an integer from 1 to 5,
  • t 0, 1, 2 or 3
  • stereoisomers as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
  • alkyl radicals represent saturated hydrocarbon radicals, in straight or branched chain, of 1 to 8 carbon atoms, in particular of 1 to 6 carbon atoms, preferably of 1 to 4 carbon atoms.
  • alkyl radicals When they are linear, mention may in particular be made of methyl, ethyl, propyl, butyl, pentyl and hexyl radicals.
  • alkyl radicals When they are branched, mention may be made especially of isopropyl, tert-butyl, 2-methylbutyl, 2-methylpentyl and 1-methylpentyl radicals.
  • aryl group is meant, in the sense of the present application, a hydrocarbon aromatic system, mono- or bicyclic of 6 to 10 carbon atoms.
  • aryl radicals there may be mentioned the phenyl or naphthyl radical, and even more particularly the phenyl radical.
  • heterocyclyclic group is meant, in the sense of the present application, a mono- or bicyclic, saturated, unsaturated or aromatic hydrocarbon system comprising one or more heteroatoms such as O, N or S.
  • Heterocyclic groups include especially heteroaryl or heterocycloalkyl groups.
  • Heteroaryl groups denote mono or bicyclic aromatic systems, having from 5 to 7 ring members (in particular 5 to 6-membered ring atoms), comprising one or more heteroatoms chosen from nitrogen, oxygen or sulfur.
  • heteroaryl radicals mention may be made of imidazolyl, pyrazinyl, thienyl, oxazolyl, furazanyl and pyrrolyl.
  • Heterocycloalkyl radicals denote mono or bicyclic saturated 5 to 7-membered (ring-atom), in particular 5 to 6-membered, systems, comprising one or more heteroatoms chosen from N, O or S.
  • heterocycloalkyls may especially mention pyrazolidine, piperidine, morpholine and piperazine.
  • the term "pharmaceutically acceptable” refers to compounds, compositions and / or dosage forms that are, within the scope of a valid medical judgment, adapted for use in contact with cells. humans and lower animals without toxicity, irritation, undue allergic response and the like, and are proportionate to a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable inorganic and organic acid addition salts, and pharmaceutically acceptable base addition salts, of the compounds of the present invention.
  • These salts include acid addition salts, i.e. organic or inorganic acid salts of a compound having a basic function such as an amine, or basic addition salts, it is i.e., alkali or organic salts of a compound having an acid function such as a carboxylic acid.
  • These salts can be prepared in situ during the final isolation and / or purification of the compounds.
  • the acid addition salts can be prepared by separately reacting the purified compound with an organic or inorganic acid and isolating the salt thus formed.
  • acid addition salts are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate and citrate salts.
  • the basic addition salts can also be prepared by separately reacting the purified compound in its acid form with an organic or inorganic base and isolating the salt thus formed.
  • Examples of basic addition salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts.
  • Sodium and potassium salts are preferred.
  • the basic addition salts may in particular be prepared from alkali or alkaline-earth metal hydrides or hydroxides which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, hydroxide of lithium, magnesium hydroxide, zinc hydroxide.
  • a first subgroup of compounds is composed of compounds for which R 1 and R 2 independently represent a hydrogen atom or a hydroxyl group,
  • a second subgroup of compounds is composed of compounds for which R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group,
  • a third subgroup of compounds is composed of compounds for which X is a group -NH- or a group 1, 4-piperydinyl,
  • a fourth subgroup of compounds is composed of compounds for which R 9 and R 10 represent a hydrogen atom.
  • a fifth subgroup of compounds consists of the compounds for which Ra, Rb, Rc, Rd, Re and Rf represents a hydrogen atom.
  • a sixth subgroup of compounds is composed of compounds for which Y is a group -NR11-, with R11 representing a hydrogen atom, a (C1-C4) alkyl group or a group - (CH 2 ) s -NH 2 where s is 1, 2 or 3.
  • a seventh subgroup of compounds is composed of compounds for which m is equal to 2, 3, 4, or 5, more preferably to 2 or 3.
  • an eighth subgroup of compounds is composed of compounds for which n is equal to 2, 3, 4 or 5, more preferably to 2, 3 or 4, and even more preferably to 2 or 3.
  • a ninth subgroup of compounds is composed of compounds for which m is different from 4.
  • a tenth subgroup of compounds is composed of compounds for which o is equal to 2 or 3.
  • an eleventh subgroup of compounds consists of compounds for which the group -NHR 'is chosen from:
  • the compounds of formula (I) are synthesized from the following bile acids:
  • the present invention relates to a compound as defined above, characterized in that it is defined by at least one of the following subgroups:
  • the present invention relates to a compound as defined above, characterized in that it represents the formula ( ⁇ )
  • R1 and R2 are as defined in claim 1 or 2
  • RI 5 and RI 6 independently represent a hydrogen atom or a (C 1 -C 8 ) alkyl group
  • n the integer 2, 3 or 4
  • n represents the integer 2, 3 or 4,
  • X represents a group -NR11- or a divalent heterocyclic group comprising one or two nitrogen atoms, with 5 or 6 members, such as a 1,4-piperazinylene group or a 1,4-piperidinylene group,
  • R 4 and R s independently represent a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2) s NH 2,
  • R5 represents a hydrogen atom, a - (CH 2 ) p -NH 2 group, a - (CH 2 ) p -NH- (CH 2 ) q -NH 2 group or a - (CH 2 ) p-NH- (CH 2) q -NH- (CH 2 ) r -NH 2, p, q, r and s independently represent an integer which can vary between
  • the present invention relates to a compound as defined above, characterized in that R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group such as a methyl or an isoproyl.
  • R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group such as a methyl or an isoproyl.
  • the present invention relates to a compound as defined above, characterized in that n is equal to 2 and m is equal to 3, n is equal to 2 and m is equal to 2, n is equal to 3 and m is equal to 4 or n is equal to 3 and m is equal to 3.
  • the present invention relates to a compound as defined above, characterized in that X represents a group - NR 11 - or a group 1, 4-piperazinylene and R 4 and R 11 independently represent an atom of hydrogen, a methyl group or a - (CH 2 ) s -NH 2 group , wherein s is 2 or 3.
  • the present invention relates to a compound as defined above, characterized in that R5 represents a hydrogen atom, a - (CH 2 ) P -NH 2 group, a - (CH 2 p-NH- (CH 2 ) q -NH 2 or - (CH 2 ) p -NH- (CH 2) q -NH- (CH 2 ) r -NH 2, where p is 2 or 3, q is equal to 2 and r is equal to 2.
  • n is equal to m.
  • the present invention also relates to a compound of formula (Ia)
  • R15, R16, R1 and R2 are as defined previously,
  • X represents an -NH- group or a 1,4-piperazinylene group
  • R5 represents a hydrogen atom or a - (CH 2 ) p -NH 2 group , with p is equal to 2 or 3,
  • the present invention relates to compounds of formula (la) for which R 5 is a hydrogen atom and R 6 is methyl or isopropyl group or R 5 and R 6 are both an ethyl group .
  • the present invention also relates to a compound of formula (Ib)
  • R15, R16, R1 and R2 are as defined previously,
  • u 0, 1, 2 or 3, preferably 1, 2 or 3,
  • R6 and R7 independently represent a hydrogen atom or a (Ci-C8) alkyl, preferably a hydrogen atom or a (Ci-C 4) alkyl,
  • stereoisomers as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
  • the present invention also relates to a compound of formula
  • R15, R16, R1, R2, n and m are as defined above, and
  • R 8 represents a (C 1 -C 8) alkyl group, preferably a methyl group, or a - (CH 2 ) s -NH 2 group , where s is an integer ranging from 1 to 5, preferably 2 or 3 , as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
  • the present invention relates to the compounds of formula (Ic) for which when R 8 represents a methyl group, then n is equal to m.
  • the present invention also relates to a compound of formula (Id)
  • R15, R16, R1 and R2 are as defined previously,
  • R5 is - (CH 2 ) p -NH 2 , where p is 2 or 3, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
  • the present invention also relates to a compound of formula
  • R15, R16, R1 and R2 are as defined previously, R5 is - (CH 2 ) p -NH 2 , where p is 2 or 3, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
  • the present invention relates to a compound of formula (Ia) and of formula (Ic) as defined above.
  • compounds representing this particular embodiment may be mentioned compounds (5) and (15) as defined below.
  • a compound of formula (I) is chosen from:
  • the compounds of the invention may exist as free bases or addition salts with pharmaceutically acceptable acids.
  • such pharmaceutically acceptable acid addition salts include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, maleate, mesylate. formate, acetate and fumarate, and more particularly the hydrochloride.
  • the compounds of formula (I), (F), (Ia), (Ib), (Ie), (Id) and (Ie) as well as the compounds (1) to (56) may be in the form of solvates such as than hydrates.
  • the invention includes these solvates.
  • a compound of formula (I), ( ⁇ ), (Ia), (Ib), (Ie), (Id) or (Ie) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.
  • a link is represented by the symbol ⁇ ⁇ ⁇ / , this means that the group carried by the carbon considered perhaps behind or in front of the representation plane of the molecule.
  • the resulting stereochemistry of carbon bearing this group may be S or R.
  • the present invention relates to a compound of formula (I), (F), (Ia), (Ib), (Ie), (Id) or (Ie) or a compound (1) to (56) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the present invention relates to a compound of formula (I), ( ⁇ ), (Ia), (Ib), (Ie), (Id) or (Ie) for its use for preventing and / or inhibiting and or treat bacterial, fungal, viral or parasitic infections in humans or animals.
  • the term “prevent” or “prevent” means that to reduce the risk of occurrence or slow down the occurrence of a given phenomenon, namely a bacterial, fungal, viral or parasitic infection.
  • the compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art.
  • the general reaction scheme described below represents a general useful method for preparing the compounds of the present invention and is not intended to limit its scope or utility.
  • the compounds of the invention may be prepared by application or adaptation of any method known per se and / or within the scope of those skilled in the art, in particular those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989 or by application or adaptation of the methods described in the examples which follow.
  • the compounds of the invention may be prepared according to Synthetic Scheme 1 below.
  • a compound of formula (IV), in which R 1 and R 2 are as defined above, is reacted in a solvent such as CH 2 Cl 2, THF or dioxane, for example in the presence of a coupling agent such as that HOBT / DCC, BOP, methyl chloroformate with a compound of formula R15R16NH, wherein R15 and RI6 are as defined above, for example at a temperature between -20 ° C and 20 ° C, to obtain a compound of formula (III).
  • a solvent such as CH 2 Cl 2, THF or dioxane
  • a coupling agent such as that HOBT / DCC, BOP, methyl chloroformate
  • the compound of formula (III) thus obtained is subjected to oxidation in the presence of a ligand, for example tri-tert-butoxide, aluminum tri-isopropoxide or Ag2C0 3 a solvent such as for example benzene, toluene, cyclohexane or trifluorotoluene, for example at a temperature between 20 ° C and 100 ° C, to obtain a compound of formula (II).
  • a ligand for example tri-tert-butoxide, aluminum tri-isopropoxide or Ag2C0 3
  • a solvent such as for example benzene, toluene, cyclohexane or trifluorotoluene, for example at a temperature between 20 ° C and 100 ° C, to obtain a compound of formula (II).
  • the compound of formula (II) thus obtained is subjected to reductive amination by reaction with a compound of formula R'NH2, in which R 'is as defined above, in the presence of a reducing agent such as titanium tetraisopropylate, zirconium tetraisopropylate, NaBH 3 CN, NaBH 4 , or a mixture of them, preferably the tetraisopropylate pair of titanium / NaBH 4 , for example at a temperature between -120 ° C and -10 ° C, preferably -80 ° C and -10 ° C, to obtain the compound of formula (I).
  • said method may also comprise the step of isolating the product obtained.
  • the compound thus prepared can be recovered from the reaction mixture by conventional means.
  • the compounds can be recovered by distilling the solvent from the reaction mixture or if necessary after distilling the solvent from the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in the reaction mixture. water, and distilling the solvent from the extract.
  • the product may, if desired, be further purified by various techniques, such as recrystallization, reprecipitation or various chromatography techniques, including column chromatography or preparative thin layer chromatography.
  • the starting compound of formula (IV) is available or may be prepared according to methods known to those skilled in the art and / or may be prepared by the application of the methods as described in the Examples or their obvious chemical equivalents .
  • the compounds of formula (I) are synthesized from the compounds of formula (IV), as defined above or bile acids:
  • the present invention also relates to the process for the preparation of the compounds of formula (I) described above, comprising a step of reductive amination of the compound of formula (II)
  • R15, R16, R1 and R2 are as defined above, with an amine of formula R'NH2, in which R 'is as defined above, in the presence of a reducing agent that may be chosen from titanium tetraisopropylate, zirconium tetraisopropylate, NaBH 3 CN, NaBH 4 , or a mixture of them, preferably the tetraisopropylate pair of titanium / NaBH 4 , to obtain said compound of formula (I).
  • a reducing agent may be chosen from titanium tetraisopropylate, zirconium tetraisopropylate, NaBH 3 CN, NaBH 4 , or a mixture of them, preferably the tetraisopropylate pair of titanium / NaBH 4 , to obtain said compound of formula (I).
  • the invention also covers a 50/50 mixture of 3 ⁇ -spermidino-N-isopropyl-chenodeoxycholamide and 3 ⁇ -N- [4'N- (3'-aminopropyl) aminobutyl] amino-N-isopropyl-chenodeoxycholamide named compound (55 ) in the following description
  • the compounds (1), (2), (5), (13), (15), (33) and (34) or a pharmaceutically acceptable salt, in particular their hydrochlorides, are particularly interesting.
  • the compounds (2), (25), (3), (20) and (30) were prepared according to the same procedure developed for the synthesis of the compound (1) using 3-oxo-N as starting precursor. isopropyl-deoxycholamide 8 and considering the appropriate polyamine chain.
  • the compounds (31), (4), (5), (26), (6) and (21) were prepared according to the same procedure developed for the synthesis of the compound (1) using as starting precursor the 3 -oxo-N-isopropyl-cholamid and considering the appropriate polyamine chain.
  • the compound (31) is obtained with a yield of 37% (C 37 H 71 N 5 O 3).
  • the compounds (31), (4), (5), (26), (6) and (21) are obtained with respective yields of 38% (C36H69N5O3), 47% (C33H62N4O3), 24% (C34H64N4O3), 40% (C37H69N5O3) and 32%.
  • the compounds (32), (7), (8), (27), (9) and (22) were prepared according to the same procedure developed for the synthesis of the compound (1) using as starting precursor the 3 -oxo-N-isopropyl-chenodeoxycholamide 9 and considering the appropriate polyamine chain.
  • the compound (32) is obtained in a yield of 51% (C 37 H 71 N 5 O 2).
  • the compounds (7), (8), (27), (9) and (22) are obtained with respective yields of 20% (C36H69N5O2), 55% (C33H62N4O2), 65% (C34H64N4O2), 15% (C37H69N5O2). ) and 26% (C37H73N7O2).
  • Example 3.5 Preparation of the compounds (33), (10), (11) and (12)
  • the compounds (33), (10), (11) and (12) were prepared according to the same procedure developed for the synthesis of compound (1) using as starting precursor 3-oxo-N-methyl-chenodeoxycholamide 13 and considering the appropriate polyamine chain.
  • the compound (33) is obtained with a yield of 36% (C35H67N5O2).
  • the compounds (10), (11) and (12) are obtained with respective yields of 58% (C34H65N5O2), 51% (C31H58N4O2) and 48% (C35H65N5O2).
  • the compounds (35), (14), (15), (28), (16) and (23) were prepared according to the same procedure developed for the synthesis of the compound (1) using as starting precursor the 3 -oxo-N-isopropyl ursodeoxycholamide 11 and considering the appropriate polyamine chain.
  • the compound (35) is obtained with a yield of 36% (C 37 H 71 N 5 O 2).
  • the compounds (14), (15), (28), (16) and (23) are obtained with yields of 44% (C36H69N5O2), 34%, (C33H62N4O2), 30% (C34H64N4O2), 53% ( C37H69N5O2) and 38% (C37H73N7O2).
  • the compound (36) is obtained in a yield of 28% (C 37 H 71 N 5 O).
  • the compounds (17), (18), (29), (19) and (24) are obtained with respective yields of 22%
  • a negative control (2 mL of sterile culture medium)
  • a positive control (1940 culture medium + 40 ⁇ , DMSO + 20 of the bacterial suspension) from a thawed biological strain (The conservation of biological strains is carried out at -80 ° C. in glycerol).
  • the tubes were incubated at 37 ° C for 24 hours at 100 rpm.
  • the germs were handled under a hood in the laboratory type L2 and before any manipulation a UV cycle was programmed and only sterile material was used.
  • a solvent toxicity test (methanol, ethanol, DMSO) was carried out and these were non-toxic at concentrations of less than or equal to 2%.
  • the chemical compounds to be tested were prepared in a mixture of DMSO / methanol (50/50) at a concentration of 5 mg / ml.
  • the optical density was carried out using a spectrophotometer at 600 nm by taking ⁇ of the bacterial suspension diluted in 900 ⁇ , sterile culture medium.
  • This test required the use of a 96-well plate and the necessary volume of the microbial suspension to be seeded was calculated for an OD corresponding to a value equal to 0.01 in each well.
  • the first line corresponded to the negative control (195 ⁇ l of sterile culture medium in each well)
  • the second line to the positive control (culture medium inoculated and supplemented with 2% DMSO)
  • the third line was loaded twice in bacterial suspension, 8 ⁇ of product to be tested were placed in each well. Subsequently, a half-cascade dilution was made from this line.
  • the first column served as an inhibition control.
  • a sterile filter was then placed on the microplate allowing the passage of gases but not contaminants.
  • the microplate was incubated at 37 ° C in a humid atmosphere for 24 hours.
  • NB The medium used is the Mueller-Hinton (MH) medium for bacteria. All tests were done in duplicate. 3) Cytotoxicity
  • the WST1 test was used to measure the cytotoxic activity of the products. It is a colorimetric test that measures the viability and rate of cell proliferation. It is based on the cleavage of colorless tetrazolium salts WST-1 (4- [3- (4-iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazole] -1,3-benzene disulfonate) by the mitochondrial dehydrogenases in yellow formazan derivative, quantifiable by spectrophotometry at 420-480 nm.
  • the WST1 test was performed on Chinese hamster ovary cells.
  • the CHO-K1 cells (ATCC, USA) are maintained in culture in Mac Coy's 5A medium supplemented with 10% fetal calf serum, 2 mM L-glutamine and a penicillin streptomycin mixture (100 U / ml). 10 ⁇ g / ml). Incubated at 37 ° C under a CO 2 -rich atmosphere (5%) and subcultured every other day.
  • the cells are transferred to 96-well plates (25,000 cells / ml) in complete Me Coy's 5A medium and maintained for 24 h at 37 ° C in a CO2 enriched wet atmosphere (5%). Increasing concentrations of test products are added to the wells in double runs and 8 growth controls containing the cells in the medium alone are included in each test run. After 24 hours at 37 ° C. (5% CO 2), the culture medium is removed, the cells are rinsed in phosphate buffer (PB S) and 50
  • PBS containing 10% WST1 reagent are added to each well. After incubation for 20 minutes at 37 ° C., the results are read spectrophotometrically at 450 nm.
  • IC50 Inhibitory Concentration
  • This method requires the use of a 96-well plate, 100 ⁇ l, a liquid culture medium is deposited in each well and then inoculated with the previously prepared microbial suspension. The volume necessary to seed is calculated for an OD of 0.01 which corresponds to approximately 5.10 6 bacteria in each well.
  • the first line corresponds to a negative control (200 of sterile culture medium in each well)
  • the second line to a positive control (100 of sterile culture medium + 100 ⁇ l, of the bacterial suspension)
  • the third line contains 192 ⁇ of culture medium, 8 ⁇ , of compound of formula (I) to be tested are placed in each well. Subsequently, cascade dilution is performed from this line.
  • doxycycline On the Gram-negative P. aeruginosa (PAO1) strain, doxycycline has a MIC of 40 ⁇ g / mL.
  • a negative control (2 ml of sterile Mueller Hinton MH culture medium)
  • a positive control (1980 ⁇ l, culture medium + 20 ⁇ l, suspension of yeasts or fungi) from a thawed biological strain (Conservation of biological strains is carried out at -80 ° C in glycerol).
  • the tubes were incubated at 37 ° C for 24 hours at 100 rpm.
  • the chemical compounds to be tested were prepared at a concentration of 5 mg / mL (as hydrochloride in water). 2) Preparation of the microplate for the determination of the minimum concentration of inhibition (MIC)
  • MIC is obtained using the cascade micro dilution method in sterile 96-well plates. Firstly, 100 ⁇ l of culture medium MH are placed in each well, then, in the first 8 ⁇ wells, the solution (5 mg / ml) of the test molecule is added. We complete in the middle to obtain a total volume of 200 ⁇ ⁇ in these wells. Serial dilution is then carried out by taking 100 ⁇ , in the first well then successively from well to well. We add by following 100 ⁇ of inoculum containing 2-6 10 5 CFU of yeasts or fungi in each well. Some wells are reserved for positive and negative controls. After 24 hours of incubation, the MIC is measured as the lowest concentration capable of inhibiting the fungal growth.
  • OD Optical Density
  • the compounds of the invention of formula (I), (F), (Ia), (Ib) or (Ie), and more particularly the compounds (1) to (56) or a salt thereof pharmaceutically acceptable demonstrate antibacterial and antifungal activity.
  • These compounds are useful for the treatment of bacterial infections, including gram-positive bacterial infections such as Staphylococcus aureus, Staphylococcus intermedius or Staphylococcus faecalis and / or Gram-negative infections such as Escherichia coli and Pseudonomas aeruginosa.
  • the compounds of formula (I), ( ⁇ ), (Ia), (Ib), (Ie) or (Id), and more particularly by the compounds (1) to (56) or one of their pharmaceutically acceptable salts according to the invention are particularly useful for the antibiotic treatment of bacterial infections, including strains of Gram-positive or Gram-negative bacteria, in humans or animals.
  • the compounds according to the invention are useful for the treatment of mastitis, metritis, dental infection, urinary tract infection, digestive disease, pyoderma or otitis in humans or the animal.
  • the compounds according to the invention are also useful as a coating preventing bacterial proliferation, for the production of products intended to destroy bio-films or to prevent their formation.
  • These compounds can be used in a medical device, for example: catheters, prostheses, implants, dialysis machines, surgical instruments, sutures or dressings.
  • Mastitis or mastitis is mammalian inflammation of the udder, it is a common infection in breeding dairy females (cows, ewes, goats, buffaloes and camels). It is characterized by the presence in milk of inflammatory cells (leucocytes) and possibly bacteria. This inflammation can have clinical consequences with a change in the appearance of the milk, visible inflammation of the udder (swelling, pain, edema) and possibly impairment of the general condition. Most often the disease remains subclinical with alteration of milk composition and decrease of production. Mastitis results from infection of the udder by bacteria more or less adapted to this biotope.
  • mastitis causes significant economic losses (unprocessed milk, unfit for use, deterioration of milk quality) and constitutes a public health risk (pathogenic bacteria and antibiotic residues). Mastitis is due to the penetration and development of a bacterium in the mammary gland. The entry of the germ is generally done by the end of the teat. Mastitis does not usually affect all quarters of the udder of the animal. The main bacteria responsible for mastitis can be grouped into two sets, depending on their contamination tank. Germs on the surface of the udder: Staphylococci, Streptococcus agalactiae, Streptococcus disgalactiae, Streptococcus uberis.
  • Metritis is an inflammation of the entire uterine wall. It can affect different species of domestic mammals (ruminants, horses, pigs, dogs, cats) and wild animals and humans. It is caused by a bacterial infection and is almost always observed after abnormal calving or significant uterine infection. Its severity ranges from a subclinical infection to a declared disease with fever and decreased milk production. In the case of cows, metritis may predispose to ketosis, abomasum displacement, and other postpartum disorders. It can also lead to a decrease in fertility, temporary or permanent, and even, in some cases, to the death of the animal.
  • Metritis is often associated with contamination of the uterus by the bacterium Arcanobacterium pyogenes, either alone or in combination with other pathogenic micro-organisms such as: Fusobacterium necrophorum, Bacteroides spp. or Escherichia coli.
  • the uterus is an ideal environment for bacterial growth.
  • up to 90% of cows are infected with uterine bacterial infections.
  • Pyoderma is a purulent skin disease, which can be acute or chronic, local or diffuse. Pyoderma is etymologically an infection of the skin. It is of external origin, caused by a bacterium, usually Staphylococcus or Streptococcus pyogenes. A pyoderma can be circumscribed or generalized. This disease is common in dogs, but can affect all species with similar pathogens, including humans. In dogs, pyotraumatic dermatitis is often observed. This is a skin lesion resulting from a compulsion to scratch, chew and lick part of the body. Once the lesion is large enough, a secondary infection by opportunistic bacteria can occur, causing the animal to bite or scratch more. Most of the animals that are often affected have allergies: especially animals allergic to fleas. However, any skin irritation can cause pyotraumatic dermatitis.
  • Periodontal disease or dental infection is a disease that can affect all species, including humans. It is the leading cause of dental disease in dogs and is common in cats. Yet characterized by bad breath, it is often unidentified by the owner. Its prevention requires regular care because it can lead to loss of teeth or serious infections. The presence of bacteria in the mouth is normal but when they grow too quickly, they can cause plaque formation. If the plaque builds up and is not cleared, gingivitis (inflammation of the gums) may occur. At this point, the treatment can be completely curative. However, in the absence of treatment, the disease progresses into periodontitis characterized by increased inflammation of the gums, scale deposits on the teeth and loss of bone and supporting structures surrounding the tooth. The attack can be managed but is irreversible. Periodontitis can lead to tooth loss and the spread of serious infections in the liver, heart or lungs.
  • Cystitis or urinary tract infection, is a disease that can affect all species including humans. This pathology is particularly common in cats but is also common in dogs. It may be secondary to local trauma such as urinary stones or infections of exogenous origin.
  • Digestive diseases, and more particularly those leading to diarrhea are very common diseases in humans and animals, especially in dogs and cats. These conditions are often due to contamination and increased bacterial proliferation of aerobic or anaerobic germs, or contamination by protozoa.
  • Otitis is an inflammation of the ear canal. Otitis can affect all animal species, as well as humans. It is an extremely common pathology in domestic carnivores, especially dogs. It can have many origins, some of which will be responsible for recurrent ear infections. Several types of Bacteria (Staphylococcus, Pseudomonas %) and yeasts (Malassezia) can develop in the ear canal, causing the appearance of otitis. These ear infections are then associated with purulent secretions and a very unpleasant odor.
  • the compounds of formula (I) are administered in combination with another antibiotic compound, in particular of the family of beta-lactams (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulphonamides, quinolones, nitro- imidazoles, derivatives of nitrofurans, benzyl-pyrimidine ring derivatives, tetracyclines or phenicolates, such as doxycycline or chloramphenicol, penicillin, ampicillin, amoxicillin, cloxacillin, dicloxacillin, oxacillin, nafcillin, Cefalexin, cefapirin, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, thimaphenicol, florfenicol, terramycin, erythromycin, spiramycin, tylosin, jos
  • the present invention thus also relates to pharmaceutical or veterinary compositions comprising at least one compound chosen from the compounds of formulas (I), (Ia), (Ib), (Ie), (Id) and (Ie) as defined above. and compounds (1) to (56) as defined above or a pharmaceutically acceptable salt of it and at least one antibiotic different from a aforementioned compound, more particularly as defined above, and even more particularly doxycycline.
  • the pharmaceutical or veterinary compositions also comprise a second antibiotic compound, in particular of the beta-lactam family (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitroimidazoles, derivatives of nitrofurans. derivatives of the benzyl-pyrimidine ring, tetracyclines or phenicolates.
  • a second antibiotic compound in particular of the beta-lactam family (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitroimidazoles, derivatives of nitrofurans. derivatives of the benzyl-pyrimidine ring, tetracyclines or phenicolates.
  • the present invention further relates to the use of compounds of formula
  • the compounds according to the invention are also compounds of choice as antibiotic substitutes.
  • the compounds according to the invention allow an excellent activity against bacteria, while avoiding the appearance of resistance, which is a major advantage as the problem of the appearance of resistance to conventional antibiotics has become a public health problem. By their mechanism of action, different from that of antibiotics, the compounds of the invention are therefore excellent as alternatives to antibiotics.
  • the compounds of formula (I), ( ⁇ ), (Ia), (Ib), (Ie) or (Id), and more particularly compounds (1) to (56) or one of their pharmaceutically acceptable salts according to the invention are especially useful for combating fungal diseases.
  • mycosis Fungal diseases are commonly referred to as mycosis. There are many types of mycosis, which differ in the fungal species involved, the location of the infection, its acute or chronic nature, the mode of infection, etc. These diseases are, for example, ringworm, candidiasis or onixys, blastomycosis, asperigllosis, coccidioidomycosis, cryptococcosis, sporotrichosis. They can affect humans or animals. Treatments are either local topical or oral, depending on the severity and type of involvement.
  • fungi frequently involved in fungal infections, especially human fungi, we find mainly: - "yeasts” (round microscopic fungi), including Candida, Cryptococcus, Pityrosporum and Pneumocystis, respectively responsible for candidiasis, cryptococcosis, pityrosporosis and pneumocystis,
  • yeasts round microscopic fungi
  • Candida Cryptococcus
  • Pityrosporum and Pneumocystis, respectively responsible for candidiasis, cryptococcosis, pityrosporosis and pneumocystis
  • filamentous fungi including dermatophytes (involved in dermatophytosis), Aspergillus (causing respiratory aspergillosis), etc., and
  • Candida infections are the leading cause of fungal infections ranging from mild infections of the skin or mucous membranes to serious organ infections. Aspergillus fungi are responsible for most infections after Candida.
  • compositions further comprise a second antiparasitic compound, in particular an antimalarial compound.
  • the invention provides compounds of formula (I), (F), (Ia), (Ib), (Ie), (Id) or (Ie) or a compound of formula (1) to (56) or a pharmaceutically acceptable salt thereof, for use in the treatment of parasitic or viral infections of humans or animals, such as malaria, feline immunodeficiency virus (FIV) Feline infectious peritonitis (FIP), toxoplasmosis, leishmaniasis, echinococcosis, ehrlichiosis, Rubarth hepatitis, leptospirosis, distemper, dog parvovirus, piroplasmosis, kennel cough or pertussis, diroflariosis, feline leukemia (FeLV), common cold, typhus or feline panleukopenia.
  • the compounds according to the invention can also be used as antiviral agent.
  • the compounds of formula (I) are administered in combination with another antimalarial compound.
  • the compounds of formula (I) make it possible to potentiate the activity of the antiparasitic compounds, in particular antimalarial compounds.
  • the present invention further relates to a method of treating a human or animal suffering from bacterial, fungal, viral or parasitic infections, which comprises at least one step of administering an effective amount of a compound according to any one of formulas (I), ( ⁇ ), (Ia), (Ib), (Ic), (Id) or (Ic) as defined above and (1) to (56) or one of its pharmaceutically acceptable salts.
  • the present invention also relates to pharmaceutical or veterinary compositions comprising at least one compound chosen from the compounds of formulas (I), (Ia), (Ib), (Ie), (Id) and (Ie) as defined above. and compounds (1) to (56) as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • compositions according to the invention may be presented in solid or liquid forms, intended, for example, for parenteral (intravenous, intramuscular, subcutaneous), oral, general, local, transmucosal, percutaneous, cutaneous, ocular, pulmonary or topical.
  • injectable solutes or suspensions or single-dose or multi-dose vials in the form of naked or coated tablets, coated tablets, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules, granules or solutions.
  • the product according to the invention also comprises one or more additional ingredients well known to those skilled in the art such as in particular, binding agents, granulation agents, lubricants, dyes, fillers, emulsifiers, minerals, film-coating agents, salts, stabilizers, buffers or vitamins.
  • Stabilizers include those substances which tend to increase the shelf life of the composition such as preservatives, emulsifiers, thickeners, packaging gases, gelling agents, humectants, sequestering agents, synergists or stabilizers.
  • suitable excipients may be cellulose or microcrystalline cellulose derivatives, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.
  • the formulation may comprise an aqueous solvent, an organic solvent or a mixture of both or a vegetable oil, an organic solvent or a mixture of both.
  • aqueous solvents water, aqueous solutes, physiological saline, isotonic solutes are the most commonly used excipients.
  • vegetable oils for example, palm oil, corn oil, cottonseed oil, sunflower oil, peanut oil, olive oil, soya oil, safflower oil, coconut oil, sesame oil, or from semi-synthetic vegetable oils obtained by fractionation and / or hydrolysis and / or total esterification of natural vegetable oils such as, for example, triglycerides fatty acid derived from vegetable oils, such as triglycerides of caprylic acid, capric acid, linoleic acid, succinic acid (sold under the trade names Miglyol ® 810, 812, 818, 820, 829), the esters of propylene glycol and fatty acid derived from vegetable oil such as esters of propylene glycol and caprylic and capric acids (sold under the trade names Miglyol ® 840), as well as their mixture, as well as esters including triacetin (glyceryl triacetate), oleate ethyl, for example.
  • natural vegetable oils such
  • organic solvents mention may be made, for example, of benzyl alcohol, ethanol, N-methyl pyrrolidone, glycerol-formal, glycofurol, diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol for example, PEG300, PEG 200 and PEG 400.
  • the selection of the vehicle is carried out so as to form liquid solutions, according to its ability to dissolve the active substance at room temperature without modifying its chemical structure and stability.
  • the chosen vehicle must be biocompatible and adapted to the injectable route.
  • the vehicle will be chosen from polar solvents, aprotic apolar solvents or their mixture.
  • the liquid injectable composition may also comprise at least one antioxidant chosen from butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), vitamin E and its derivatives, propylgallate and mixtures thereof.
  • cocoa butter or polyethylene glycol stearates are the preferred excipients.
  • the usual excipients are aqueous solvents , alcoholic, polar or otherwise, which promote transcutaneous passage, such as water, benzyl alcohol, vegetable and mineral oils, resuspension agents, antioxidants, surfactants, including a mixture of alcohol benzyl and / or labrasol and / or propylene glycol laurate as a penetrating agent may be used.
  • aqueous solvents such as water, benzyl alcohol, vegetable and mineral oils, resuspension agents, antioxidants, surfactants, including a mixture of alcohol benzyl and / or labrasol and / or propylene glycol laurate as a penetrating agent may be used.
  • the appropriate excipients may also be selected by those skilled in the art depending on the specificities required.
  • the dosage may vary within the important limits (0.05 mg to 1000 mg) depending on the therapeutic indication and the route of administration, as well as the age and weight of the subject.
  • the present invention also relates to the use of at least one compound selected from a compound of any one of formulas (I), (I '), (Ia), (Ib), (Ie), (Id) and (le) as defined above, and the compounds (1) to (56) as defined above, or a pharmaceutically acceptable salt thereof according to the present invention for the manufacture of a pharmaceutical or veterinary composition intended for the prevention and / or treatment of a bacterial, fungal, viral or parasitic infection.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a compound of formula (I), in which R' represents a -(CRaRb)n-X-(CRcRd)m-[Y-(CReRf)o]t-NR9R10 group, and X and Y independently represent a -NR11- group, an –O- group or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members; as well as the stereoisomers, stereoisomer mixtures, and/or pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical or veterinary compositions containing same, and to the use of said compositions as a drug, more particularly in the treatment of bacterial, fungal, viral or parasitic infections. The invention further relates to the pharmaceutical or veterinary compositions comprising such a compound of formula (I) in combination with an antibiotic different from such a compound of formula (I).

Description

DERIVES AMIDES DE SOUAL AMINE POUR LE TRAITEMENT DES  AMINO ACID AMINO DERIVATIVES FOR THE TREATMENT OF
INFECTIONS  INFECTIONS
La présente invention concerne des analogues de la squalamine pour leur utilisation dans le traitement des infections bactériennes, fongiques, virales ou parasitaires chez l'homme ou l'animal, ainsi que les compositions pharmaceutiques ou vétérinaires les comprenant. The present invention relates to squalamine analogs for use in the treatment of bacterial, fungal, viral or parasitic infections in humans or animals, as well as pharmaceutical or veterinary compositions comprising them.
En 1993, la squalamine, un stéroïde naturel, isolée majoritairement des tissus d'un petit requin Squalus acanthias, s'est révélée être une substance très active présentant essentiellement une activité antiangiogénique contre les cellules et une activité anti virale et antibactérienne.  In 1993, squalamine, a natural steroid, mostly isolated from the tissues of a small shark Squalus acanthias, was found to be a very active substance with essentially anti-angiogenic activity against cells and anti-viral and antibacterial activity.
Figure imgf000003_0001
Squalamine
Figure imgf000003_0001
squalamine
Chimiquement, la squalamine est une molécule originale présentant un caractère amphiphile. Elle comporte ainsi, une partie centrale apolaire (un squelette de type cholestane) et deux extrémités polaires (une chaîne polyamine et un groupement sulfate).  Chemically, squalamine is an original molecule with an amphiphilic character. It thus comprises an apolar central portion (a cholestane-type skeleton) and two polar ends (a polyamine chain and a sulfate group).
Initialement, ce polyaminostérol hydrosoluble avait suscité l'intérêt pour ses propriétés antiangiogéniques et antimicrobiennes sur une variété de bactéries à Gram positif (Staphylococcus aureus, Enterococcus faecalis) et à Gram négatif (Escherichia coli, Pseudomonas aeruginosa), des champignons (Candia albicans, Candida tropicalis) et des protozoaires.  Initially, this water-soluble polyaminosterol had generated interest in its antiangiogenic and antimicrobial properties on a variety of Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, fungi (Candia albicans, Candida). tropicalis) and protozoa.
La source naturelle de la squalamine étant limitée, on a recherché des dérivés synthétiques analogues aminostéroïdiens de la squalamine. On a décrit notamment des dérivés ou analogues comportant une chaîne polyaminée en position 3 ou 7 de cycles 10, 13 diméthyl, 17 octane cholestane ou cholestène, éventuellement hydroxylés en position 7 ou respectivement 3. En particulier, des dérivés de formule Ha - Ilb - Ile - Ild et II- 1 ci- après ont été décrits comme présentant une activité antibactérienne similaire à la squalamine vis-à-vis de diverses bactéries Gram positif et Gram négatif multirésistantes. Since the natural source of squalamine is limited, synthetic analogues of aminosteroid derivatives of squalamine have been investigated. In particular, derivatives or analogs comprising a polyamine chain at the 3- or 7-position of 10, 13 dimethyl, 17 octane cholestane or cholestene rings, optionally hydroxylated in position 7 or 3, are described. In particular, derivatives of formula IIa - IIb - Ile-Ild and II-1 hereinafter have been reported to have similar squalamine-like antibacterial activity to various multiresistant Gram-positive and Gram-negative bacteria.
Figure imgf000004_0001
Figure imgf000004_0001
On a plus particulièrement suggéré une application de ces dérivés pour un traitement curatif des infections pulmonaires par voie aérosol. Cependant, la Demanderesse a observé que ces composés présentaient une cytotoxicité importante et que les composés de formule Ile et Ild présentaient une faible activité contre certaines bactéries gram- négatives telles que E. coli.  It has been particularly suggested an application of these derivatives for a curative treatment of pulmonary infections by aerosol. However, the Applicant has observed that these compounds have a high cytotoxicity and that the compounds of formula Ile and Ild have a low activity against certain gram-negative bacteria such as E. coli.
On connaît en particulier de WO 2011/067501 des dérivés aminostéroïdiens antibactériens de type polyamino cholestane ou cholestène pour une application par voie topique locale, pour la décolonisation cutanéo-muqueuse rapide de Staphylococcus aureus, notamment sous la forme de pommade ou de crème.  Antibacterial aminosteroid derivatives of the polyamino cholestane or cholestene type are especially known for topical application locally, for the fast cutaneous-mucous decolonization of Staphylococcus aureus, especially in the form of ointment or cream.
Le brevet US 5,856,535 décrit par ailleurs des esters d'aminostérols, dont certains présentent entre autres des activités d'inhibition de l'angiogénèse, des activités antiprolifératives ou encore des activités antibactériennes. Toutefois aucun des composés décrits dans ce document ne sont en particulier des amides.  US Pat. No. 5,856,535 also describes aminosterol esters, some of which, inter alia, exhibit angiogenesis inhibition activities, antiproliferative activities or even antibacterial activities. However none of the compounds described in this document are in particular amides.
On connaît également les documents Wen-Hua Chen et al « A bioconjugate approach toward squalamine mimics: insight into the mechanism of the biological action », Bioconjugate Chemistry, vol. 17, no. 6, 1582-1591 et AM Bellini et al « Antimicrobial activity of basic cholane derivatives part IX », Archiv des Pharmazie, vol. 323, no. 4, 201- 205. Toutefois, ces documents décrivent non seulement des composés structurellement éloignés des composés de la présente invention mais encore ne présentant pas d'activités antimicrobiennes intéressantes. Il a maintenant été découvert des composés analogues de la squalamine, présentant une bonne activité antibactérienne contre des bactéries gram-positives et gram- négatives, tout en étant avantageusement moins cytotoxiques que la squalamine. Cette nouvelle famille de molécules, grâce à sa structure chimique, présente une meilleure stabilité chimique que les composés décrits dans US 5,856,535. Also known are Wen-Hua Chen et al. Bioconjugate approach to squalamine mimics: insight into the mechanism of biological action, Bioconjugate Chemistry, vol. 17, no. 6, 1582-1591 and AM Bellini et al., "Antimicrobial activity of basic cholane derivatives part IX", Archiv des Pharmazie, vol. 323, no. 4, 201-205. However, these documents describe not only compounds structurally distant from the compounds of the present invention but also not exhibiting interesting antimicrobial activities. Squalamine-like compounds have now been found to exhibit good antibacterial activity against gram-positive and gram-negative bacteria, while being less cytotoxic than squalamine. This new family of molecules, thanks to its chemical structure, has a better chemical stability than the compounds described in US Pat. No. 5,856,535.
Ces composés ont une activité intéressante pour prévenir et/ou inhiber et/ou traiter les infections bactériennes, fongiques, virales ou parasitaires chez l'homme ou l'animal. Ces composés sont également des composés de choix en tant que substituts aux antibiotiques. Selon un mode de réalisation particulier de l'invention, elle est destinée aux mammifères domestiques tels que ruminants, chevaux, porcins, chiens et chats et aux animaux sauvages. Selon un mode de réalisation encore plus particulier elle est destinée aux animaux de compagnie, encore plus précisément aux chiens et aux chats, ou encore aux rongeurs, et s'adresse plus particulièrement aux chiens et aux chats.  These compounds have an interesting activity for preventing and / or inhibiting and / or treating bacterial, fungal, viral or parasitic infections in humans or animals. These compounds are also compounds of choice as antibiotic substitutes. According to a particular embodiment of the invention, it is intended for domestic mammals such as ruminants, horses, pigs, dogs and cats and wild animals. According to an even more particular embodiment it is intended for pets, more specifically for dogs and cats, or even rodents, and is more particularly for dogs and cats.
Les composés selon l'invention permettent une excellente activité contre les bactéries, tout en évitant l'apparition de résistances, qui est un atout majeur tant le problème de l'apparition de résistances aux antibiotiques classiques est devenu un problème de santé publique. De par leur mécanisme d'action, différent de celui des antibiotiques, les composés de l'invention se présentent donc comme d'excellents substituts aux antibiotiques.  The compounds according to the invention allow an excellent activity against bacteria, while avoiding the appearance of resistance, which is a major advantage as the problem of the appearance of resistance to conventional antibiotics has become a public health problem. By their mechanism of action, different from that of antibiotics, the compounds of the invention are therefore excellent as alternatives to antibiotics.
Ainsi, selon un premier aspect, la présente invention est relative à un composé de formule Thus, according to a first aspect, the present invention relates to a compound of formula
Figure imgf000005_0001
Figure imgf000005_0001
dans laquelle  in which
RI et R2 représentent indépendamment un atome d'hydrogène, un groupe R1 and R2 independently represent a hydrogen atom, a group
SO3H ou un groupe hydroxy, SO3H or a hydroxy group,
R' représente un groupe -(CRaRb)n-X-(CRcRd)m-[Y-(CReRf)o]t-NR9Rio, Pa, Rb, Rc, Pd, Pe et Rf représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe (C6-Cio)aryle, R 'represents a group - (CRaRb) nX- (CRcRd) m- [Y- (CReRf) o] t -NR9Rio, Pa, Rb, Rc, Pd, Pe and Rf independently represent a hydrogen atom, a (Ci-Cs) alkyl group or a (C 6 -Cio) aryl group,
X et Y représentent indépendamment un groupe -NR1 1-, un groupe -O- ou un groupe hétérocyclique divalent comprenant au moins un atome d'azote, à 5 ou 6 chaînons,  X and Y independently represent a group -NR1 1-, a group -O- or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members,
R9 et RIO représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou forment ensemble, avec l'atome d'azote qui les porte, un groupe hétérocyclique à 5 ou 6 chaînons, éventuellement substitué par un ou deux groupe(s) =0 ou =S,  R 9 and R 10 independently represent a hydrogen atom, a (C 1 -C 5) alkyl group or together with the nitrogen atom which carries them a 5- or 6-membered heterocyclic group, optionally substituted by one or two groups (s) = 0 or = S,
Rl l représente un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe -(CH2)S-NH2, R 1 represents a hydrogen atom, a (C 1 -C 5) alkyl group or a - (CH 2 ) S -NH 2 group ,
RI 5 et RI 6 représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe (C6-Cio)aryle, RI 5 and RI 6 independently represent a hydrogen atom, a (C 1 -C 5) alkyl group or a (C 6 -C 10) aryl group,
n, m, o et s représentent indépendamment un nombre entier compris entre 1 et 5,  n, m, o and s independently represent an integer from 1 to 5,
t est égal à 0, 1 , 2 ou 3,  t is 0, 1, 2 or 3,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci.  as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
Dans le contexte de la présente invention : In the context of the present invention:
- Les radicaux « alkyles » représentent des radicaux hydrocarbonés saturés, en chaîne droite ou ramifiée, de 1 à 8 atomes de carbone, notamment de 1 à 6 atomes de carbone, de préférence de 1 à 4 atomes de carbone. On peut notamment citer, lorsqu'ils sont linéaires, les radicaux méthyle, éthyle, propyle, butyle, pentyle, hexyle. On peut notamment citer, lorsqu'ils sont ramifiés, les radicaux isopropyle, tert-butyl, 2- méthylbutyle, 2-méthylpentyle et 1-méthylpentyle.  The "alkyl" radicals represent saturated hydrocarbon radicals, in straight or branched chain, of 1 to 8 carbon atoms, in particular of 1 to 6 carbon atoms, preferably of 1 to 4 carbon atoms. When they are linear, mention may in particular be made of methyl, ethyl, propyl, butyl, pentyl and hexyl radicals. When they are branched, mention may be made especially of isopropyl, tert-butyl, 2-methylbutyl, 2-methylpentyl and 1-methylpentyl radicals.
- Par groupe « aryle », on entend, au sens de la présente demande, un système aromatique hydrocarboné, mono ou bicyclique de 6 à 10 atomes de carbone. Parmi les radicaux aryles, on peut notamment citer le radical phényle ou naphtyle, et encore plus particulièrement le radical phényle.  By "aryl" group is meant, in the sense of the present application, a hydrocarbon aromatic system, mono- or bicyclic of 6 to 10 carbon atoms. Among the aryl radicals, there may be mentioned the phenyl or naphthyl radical, and even more particularly the phenyl radical.
- Par groupe « hétérocyclyclique », on entend, au sens de la présente demande, un système hydrocarboné mono-, ou bicyclique, saturé, insaturé ou aromatique comprenant un ou plusieurs hétéroatomes tels que O, N ou S. Les groupes hétérocycliques incluent notamment les groupes hétéroaryle ou hétérocycloalkyle. By "heterocyclyclic" group is meant, in the sense of the present application, a mono- or bicyclic, saturated, unsaturated or aromatic hydrocarbon system comprising one or more heteroatoms such as O, N or S. Heterocyclic groups include especially heteroaryl or heterocycloalkyl groups.
- Les groupes « hétéroaryles » désignent les systèmes aromatiques mono ou bicyclique, et ayant de 5 à 7 chaînons (atomes de cycle), notamment de 5 à 6 chaînons, comprenant un ou plusieurs hétéroatomes choisis parmi l'azote, l'oxygène ou le soufre. Parmi les radicaux hétéroaryles, on peut citer l'imidazolyle, le pyrazinyle, le thiényle, l'oxazolyle, le furazanyle et le pyrrolyle.  "Heteroaryl" groups denote mono or bicyclic aromatic systems, having from 5 to 7 ring members (in particular 5 to 6-membered ring atoms), comprising one or more heteroatoms chosen from nitrogen, oxygen or sulfur. Among the heteroaryl radicals, mention may be made of imidazolyl, pyrazinyl, thienyl, oxazolyl, furazanyl and pyrrolyl.
- Les radicaux « hétérocycloalkyles » désignent les systèmes mono ou bicycliques, saturés de 5 à 7 chaînons (atomes de cycle), notamment de 5 à 6 chaînons, comprenant un ou plusieurs hétéroatomes choisis parmi N, O ou S. Parmi les hétérocycloalkyles, on peut notamment citer la pyrazolidine, la pipéridine, la morpholine et la pipérazine.  "Heterocycloalkyl" radicals denote mono or bicyclic saturated 5 to 7-membered (ring-atom), in particular 5 to 6-membered, systems, comprising one or more heteroatoms chosen from N, O or S. Among heterocycloalkyls, may especially mention pyrazolidine, piperidine, morpholine and piperazine.
- Tel qu'il est utilisé ici, le terme «pharmaceutiquement acceptable» se réfère à des composés, compositions et/ou formes de dosage qui sont, dans la portée d'un jugement médical valable, adapté pour une utilisation en contact avec les cellules des humains et des animaux inférieurs sans toxicité, irritation, réponse allergique indue et similaires, et sont proportionnés à un rapport avantage/risque raisonnable.  As used herein, the term "pharmaceutically acceptable" refers to compounds, compositions and / or dosage forms that are, within the scope of a valid medical judgment, adapted for use in contact with cells. humans and lower animals without toxicity, irritation, undue allergic response and the like, and are proportionate to a reasonable benefit / risk ratio.
- L'expression « sels pharmaceutiquement acceptables » fait référence aux sels d'addition d'acides inorganiques et organiques, pharmaceutiquement acceptables, et les sels d'addition de bases pharmaceutiquement acceptables, des composés de la présente invention. Ces sels incluent des sels d'addition acides, c'est-à-dire des sels d'acide organique ou minéral d'un composé comportant une fonction basique telle qu'une aminé, ou des sels d'addition basiques, c'est-à-dire des sels alcalins ou organiques d'un composé comportant une fonction acide telle qu'un acide carboxylique. Ces sels peuvent être préparés in situ pendant l'isolement final et/ou la purification des composés. En particulier, les sels d'addition acide peuvent être préparés en faisant réagir séparément le composé purifié avec un acide organique ou inorganique et en isolant le sel ainsi formé. Parmi les exemples de sels d'addition acide on trouve les sels bromhydrate, chlorhydrate, sulfate, bisulfate, phosphate, nitrate, acétate, oxalate, valerate, oléate, palmitate, stéarate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maléate, fumarate, succinate, tartrate, naphthylate, mésylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, méthylènebis-b-hydroxynaphtoates, acide gentisique, iséthionates, di-p- toluoyltartrates, methanesulfonates, éthanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates et quinateslaurylsulfonate, et analogues. (Voir par exemple S.M. Berge et al. « Pharmaceutical Salts » J. Pharm. Sci, 66 :p.1-19 (1977)). The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable inorganic and organic acid addition salts, and pharmaceutically acceptable base addition salts, of the compounds of the present invention. These salts include acid addition salts, i.e. organic or inorganic acid salts of a compound having a basic function such as an amine, or basic addition salts, it is i.e., alkali or organic salts of a compound having an acid function such as a carboxylic acid. These salts can be prepared in situ during the final isolation and / or purification of the compounds. In particular, the acid addition salts can be prepared by separately reacting the purified compound with an organic or inorganic acid and isolating the salt thus formed. Examples of the acid addition salts are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate and citrate salts. , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphthoates, gentisic acid, isethionates, di-p- toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinateslaurylsulfonate, and the like. (See, for example, SM Berge et al., "Pharmaceutical Salts" J. Pharm Sci, 66: p.1-19 (1977)).
- Les sels d'addition basiques peuvent également être préparés en faisant réagir séparément le composé purifié sous sa forme acide avec une base organique ou inorganique et en isolant le sel ainsi formé. Des exemples de sels d'addition basiques comprennent les sels de sodium, potassium, calcium, baryum, zinc, magnésium et aluminium. Les sels de sodium et de potassium sont préférés. Les sels d'addition basiques peuvent notamment être préparés à partir d'hydrures ou d'hydroxydes de métal alcalin ou alcalino -terreux qui comprennent hydrure de sodium, hydroxyde de sodium, hydroxyde de potassium, hydroxyde de calcium, hydroxyde d'aluminium, hydroxyde de lithium, hydroxyde de magnésium, hydroxyde de zinc.  The basic addition salts can also be prepared by separately reacting the purified compound in its acid form with an organic or inorganic base and isolating the salt thus formed. Examples of basic addition salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Sodium and potassium salts are preferred. The basic addition salts may in particular be prepared from alkali or alkaline-earth metal hydrides or hydroxides which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, hydroxide of lithium, magnesium hydroxide, zinc hydroxide.
Parmi les composés de formule générale (I), un premier sous-groupe de composés est constitué des composés pour lesquels RI et R2 représentent indépendamment un atome d'hydrogène ou un groupe hydroxy, Among the compounds of general formula (I), a first subgroup of compounds is composed of compounds for which R 1 and R 2 independently represent a hydrogen atom or a hydroxyl group,
Parmi les composés de formule générale (I), un deuxième sous-groupe de composés est constitué des composés pour lesquels RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C4)alkyle,  Among the compounds of general formula (I), a second subgroup of compounds is composed of compounds for which R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group,
Parmi les composés de formule générale (I), un troisième sous-groupe de composés est constitué des composés pour lesquels X est un groupe -NH- ou un groupe 1 ,4-piperydinyle,  Among the compounds of general formula (I), a third subgroup of compounds is composed of compounds for which X is a group -NH- or a group 1, 4-piperydinyl,
Parmi les composés de formule générale (I), un quatrième sous-groupe de composés est constitué des composés pour lesquels R9 et RIO représentent un atome d'hydrogène.  Among the compounds of general formula (I), a fourth subgroup of compounds is composed of compounds for which R 9 and R 10 represent a hydrogen atom.
Parmi les composés de formule générale (I), un cinquième sous-groupe de composés est constitué des composés pour lesquels Ra, Rb, Rc, Rd, Re et Rf représente un atome d'hydrogène. Among the compounds of general formula (I), a fifth subgroup of compounds consists of the compounds for which Ra, Rb, Rc, Rd, Re and Rf represents a hydrogen atom.
Parmi les composés de formule générale (I), un sixième sous-groupe de composés est constitué des composés pour lesquels Y est un groupe -NR11-, avec Rl l représentant un atome d'hydrogène, un groupe (Ci-C4)alkyle ou un groupe -(CH2)s-NH2 où s est égal à 1, 2 ou 3. Parmi les composés de formule générale (I), un septième sous-groupe de composés est constitué des composés pour lesquels m est égal à 2, 3, 4, ou 5, plus préférentiellement à 2 ou 3. Among the compounds of general formula (I), a sixth subgroup of compounds is composed of compounds for which Y is a group -NR11-, with R11 representing a hydrogen atom, a (C1-C4) alkyl group or a group - (CH 2 ) s -NH 2 where s is 1, 2 or 3. Among the compounds of general formula (I), a seventh subgroup of compounds is composed of compounds for which m is equal to 2, 3, 4, or 5, more preferably to 2 or 3.
Parmi les composés de formule générale (I), un huitième sous-groupe de composés est constitué des composés pour lesquels n est égal à 2, 3, 4 ou 5, plus préférentiellement à 2, 3 ou 4, et encore plus préférentiellement à 2 ou 3.  Among the compounds of general formula (I), an eighth subgroup of compounds is composed of compounds for which n is equal to 2, 3, 4 or 5, more preferably to 2, 3 or 4, and even more preferably to 2 or 3.
Parmi les composés de formule générale (I), un neuvième sous-groupe de composés est constitué des composés pour lesquels m est différent de 4.  Among the compounds of general formula (I), a ninth subgroup of compounds is composed of compounds for which m is different from 4.
Parmi les composés de formule générale (I), un dixième sous-groupe de composés est constitué des composés pour lesquels o est égal à 2 ou 3.  Among the compounds of general formula (I), a tenth subgroup of compounds is composed of compounds for which o is equal to 2 or 3.
Parmi les composés de formule générale (I), un onzième sous-groupe de composés est constitué des composés pour lesquels le groupe -NHR' est choisi parmi :  Among the compounds of general formula (I), an eleventh subgroup of compounds consists of compounds for which the group -NHR 'is chosen from:
Figure imgf000009_0001
Figure imgf000009_0001
Selon une variante préférée, les composés de formule (I) sont synthétisés partir des acides biliaires suivants :
Figure imgf000010_0001
According to a preferred variant, the compounds of formula (I) are synthesized from the following bile acids:
Figure imgf000010_0001
Les sous-groupes définis ci-dessus, pris isolément ou en combinaison, font également partie de l'invention. The subgroups defined above, taken alone or in combination, are also part of the invention.
Dès lors, la présente invention concerne un composé tel que défini précédemment, caractérisé en ce qu'il est défini par au moins l'un des sous-groupes suivants :  Therefore, the present invention relates to a compound as defined above, characterized in that it is defined by at least one of the following subgroups:
- premier sous-groupe de composés de formule (I) lesquels RI et R2 représentent indépendamment un atome d'hydrogène ou un groupe hydroxy,  - first subgroup of compounds of formula (I) which RI and R2 independently represent a hydrogen atom or a hydroxy group,
- deuxième sous-groupe de composés de formule (I) pour lesquels RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C4)alkyle,  second subgroup of compounds of formula (I) for which R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group,
- troisième sous-groupe de composés de formule (I) pour lesquels X est un groupe -NH-, un groupe hétérocyclique à 6 chaînons comportant un ou deux atomes d'azote, de préférence un groupe 1 ,4-pipérazinylene ou un groupe 1 ,4-pipéridinylene,  third subgroup of compounds of formula (I) for which X is a group -NH-, a 6-membered heterocyclic group containing one or two nitrogen atoms, preferably a 1,4-piperazinylene group or a group 1 , 4-piperidinylene,
- quatrième sous-groupe de composés de formule (I) pour lesquels R9 et RIO représentent un atome d'hydrogène,  fourth subgroup of compounds of formula (I) for which R 9 and R 10 represent a hydrogen atom,
- cinquième sous-groupe de composés de formule (I) pour lesquels Ra, Rb, Rc, Rd, Re et Rf représentent un atome d'hydrogène,  fifth subgroup of compounds of formula (I) for which Ra, Rb, Rc, Rd, Re and Rf represent a hydrogen atom,
- sixième sous-groupe de composés de formule (I) pour lesquels Y est un groupe -NR11-, avec RI 1 représentant un atome d'hydrogène, un groupe (Ci-C4)alkyle ou un groupe -(CH2)s-NH2 où s est égal à 1, 2 ou 3, sixth subset of compounds of formula (I) for which Y is a group -NR 11 -, with R 1 representing a hydrogen atom, a (C 1 -C 4) alkyl group or a - (CH 2 ) s group; NH 2 where s is 1, 2 or 3,
- septième sous-groupe de composés de formule (I) pour lesquels m est égal à 2, 3, 4, ou 5, plus préférentiellement à 2 ou 3, - huitième sous-groupe de composés de formule (I) pour lesquels n est égal à 2, 3, 4 ou 5, plus préférentiellement à 2, 3 ou 4, seventh subgroup of compounds of formula (I) for which m is 2, 3, 4, or 5, more preferably 2 or 3, eighth subgroup of compounds of formula (I) for which n is 2, 3, 4 or 5, more preferably 2, 3 or 4,
- neuvième sous-groupe de composés de formule (I) pour lesquels m est différente de 4,  ninth subgroup of compounds of formula (I) for which m is not equal to 4,
- dixième sous-groupe de composés de formule (I) pour lesquels o est égal à 2 ou 3,  tenth subgroup of compounds of formula (I) for which o is 2 or 3,
- onzième sous-groupe de composés de formule (I) pour lesquels le groupe - NHR' est choisi parmi :  eleventh subgroup of compounds of formula (I) for which the group - NHR 'is chosen from:
Figure imgf000011_0001
Figure imgf000011_0001
ou or
- ou par la combinaison des sous-groupes tels que définis ci-dessus.  or by the combination of the subgroups as defined above.
Selon un mode de réalisation particulier, la présente invention est relative à un composé tel que défini précédemment, caractérisé en ce qu'il représente la formule (Γ) According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that it represents the formula (Γ)
dans laquelle in which
RI et R2 sont tels que définis en revendication 1 ou 2,  R1 and R2 are as defined in claim 1 or 2,
RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C8)alkyle, RI 5 and RI 6 independently represent a hydrogen atom or a (C 1 -C 8 ) alkyl group,
n représente le nombre entier 2, 3 ou 4,  n represents the integer 2, 3 or 4,
m représente le nombre entier 2, 3 ou 4,  m represents the integer 2, 3 or 4,
X représente un groupe -NR11- ou un groupe hétérocyclique divalent comprenant un ou deux atomes d'azote, à 5 ou 6 chaînons, tel qu'un groupe 1 ,4-pipérazinylene ou un groupe 1 ,4-pipéridinylene,  X represents a group -NR11- or a divalent heterocyclic group comprising one or two nitrogen atoms, with 5 or 6 members, such as a 1,4-piperazinylene group or a 1,4-piperidinylene group,
R4 et Rl l représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe -(CH2)s-NH2, R 4 and R s independently represent a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2) s NH 2,
R5 représente un atome d'hydrogène, un groupe -(CH2)P-NH2, un groupe -(CH2)p-NH-(CH2)q-NH2 ou un groupe -(CH2)p-NH-(CH2)q-NH-(CH2)r-NH2, p, q, r et s représentent indépendamment un nombre entier pouvant varier entreR5 represents a hydrogen atom, a - (CH 2 ) p -NH 2 group, a - (CH 2 ) p -NH- (CH 2 ) q -NH 2 group or a - (CH 2 ) p-NH- (CH 2) q -NH- (CH 2 ) r -NH 2, p, q, r and s independently represent an integer which can vary between
1 et 5, 1 and 5,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci. Parmi les composés de formule (I) et (Γ) on préfère les composés pour lesquels n et m sont égaux à 3.  as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof. Among the compounds of formula (I) and (Γ), those compounds for which n and m are equal to 3 are preferred.
Selon un mode de réalisation particulier, la présente invention est relative à un composé tel que défini précédemment, caractérisé en ce que RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C4)alkyle tel qu'un méthyle ou un isoproyle. Selon un mode de réalisation particulier, la présente invention est relative à un composé tel que défini précédemment, caractérisé en ce que n est égal à 2 et m est égal à 3, n est égal à 2 et m est égal à 2, n est égale à 3 et m est égal à 4 ou bien n est égal à 3 et m est égal à 3. According to one particular embodiment, the present invention relates to a compound as defined above, characterized in that R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group such as a methyl or an isoproyl. According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that n is equal to 2 and m is equal to 3, n is equal to 2 and m is equal to 2, n is equal to 3 and m is equal to 4 or n is equal to 3 and m is equal to 3.
Selon un mode de réalisation particulier, la présente invention est relative à un composé tel que défini précédemment, caractérisé en ce que X représente un groupe - NR11- ou un groupe 1 ,4-pipérazinylene et R4 et Rl l représentant indépendamment un atome d'hydrogène, un groupe méthyle ou un groupe -(CH2)s-NH2, dans lequel s est égal à 2 ou 3. According to one particular embodiment, the present invention relates to a compound as defined above, characterized in that X represents a group - NR 11 - or a group 1, 4-piperazinylene and R 4 and R 11 independently represent an atom of hydrogen, a methyl group or a - (CH 2 ) s -NH 2 group , wherein s is 2 or 3.
Selon un mode de réalisation particulier, la présente invention est relative à un composé tel que défini précédemment, caractérisé en ce que R5 représente un atome d'hydrogène, un groupe -(CH2)P-NH2, un groupe -(CH2)p-NH-(CH2)q-NH2 ou un groupe -(CH2)p-NH-(CH2)q-NH-(CH2)r-NH2, avec p est égal à 2 ou 3, q est égal à 2 et r est égal à 2. According to a particular embodiment, the present invention relates to a compound as defined above, characterized in that R5 represents a hydrogen atom, a - (CH 2 ) P -NH 2 group, a - (CH 2 p-NH- (CH 2 ) q -NH 2 or - (CH 2 ) p -NH- (CH 2) q -NH- (CH 2 ) r -NH 2, where p is 2 or 3, q is equal to 2 and r is equal to 2.
Selon un mode de réalisation particulier n est égal à m. According to a particular embodiment n is equal to m.
La présente invention est également relative à un composé de formule (la)  The present invention also relates to a compound of formula (Ia)
Figure imgf000013_0001
(la) dans laquelle
Figure imgf000013_0001
(la) in which
R15, R16, RI et R2 sont tels que définis précédemment,  R15, R16, R1 and R2 are as defined previously,
X représente un groupe -NH- ou un groupe 1 ,4-pipérazinylene,  X represents an -NH- group or a 1,4-piperazinylene group,
R5 représente un atome d'hydrogène ou un groupe -(CH2)P-NH2, avec p est égal à 2 ou 3, R5 represents a hydrogen atom or a - (CH 2 ) p -NH 2 group , with p is equal to 2 or 3,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci. Selon un mode de réalisation préféré, la présente invention porte sur composés de formule (la) pour lesquels RI 5 est un atome d'hydrogène et RI 6 est groupe méthyle ou isopropyle ou encore RI 5 et RI 6 sont tous les deux un groupe éthyle. as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof. According to a preferred embodiment, the present invention relates to compounds of formula (la) for which R 5 is a hydrogen atom and R 6 is methyl or isopropyl group or R 5 and R 6 are both an ethyl group .
La présente invention est également relative à un composé de formule (Ib) The present invention also relates to a compound of formula (Ib)
Figure imgf000014_0001
Figure imgf000014_0001
dans laquelle  in which
R15, R16, RI et R2 sont tels que définis précédemment,  R15, R16, R1 and R2 are as defined previously,
u est égal à 0, 1, 2 ou 3, préférentiellement à 1, 2 ou 3,  u is 0, 1, 2 or 3, preferably 1, 2 or 3,
R6 et R7 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C8)alkyle, de préférence un atome d'hydrogène ou un groupe (Ci-C4)alkyle, R6 and R7 independently represent a hydrogen atom or a (Ci-C8) alkyl, preferably a hydrogen atom or a (Ci-C 4) alkyl,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci.  as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
La présente invention est également relative à un composé de formule (le) The present invention also relates to a compound of formula
Figure imgf000014_0002
Figure imgf000014_0002
dans laquelle  in which
R15, R16, RI, R2, n et m sont tels que définis précédemment, et  R15, R16, R1, R2, n and m are as defined above, and
R8 représente un groupe (Ci-C8)alkyle, de préférence un groupe méthyle, ou un groupe -(CH2)s-NH2, avec s étant un nombre entier pouvant varier entre 1 et 5, de préférence égal à 2 ou 3, ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci. R 8 represents a (C 1 -C 8) alkyl group, preferably a methyl group, or a - (CH 2 ) s -NH 2 group , where s is an integer ranging from 1 to 5, preferably 2 or 3 , as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
Selon un mode de réalisation préféré, la présente invention porte sur les composés de formule (le) pour lesquels lorsque R8 représente un groupe -(CH2)SNH2, alors n =m=s. According to a preferred embodiment, the present invention relates to the compounds of formula (Ic) for which when R 8 represents a group - (CH 2 ) S NH 2 , then n = m = s.
Selon un mode de réalisation préféré, la présente invention porte sur les composés de formule (le) pour lesquels lorsque R8 représente un groupe méthyle, alors n est égal à m.  According to a preferred embodiment, the present invention relates to the compounds of formula (Ic) for which when R 8 represents a methyl group, then n is equal to m.
La présente invention est également relative à un composé de formule (Id) The present invention also relates to a compound of formula (Id)
Figure imgf000015_0001
Figure imgf000015_0001
dans laquelle  in which
R15, R16, RI et R2 sont tels que définis précédemment,  R15, R16, R1 and R2 are as defined previously,
R5 représente un groupe -(CH2)P-NH2, avec p est égal à 2 ou 3, ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci. R5 is - (CH 2 ) p -NH 2 , where p is 2 or 3, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
La présente invention est également relative à un composé de formule (le) The present invention also relates to a compound of formula
Figure imgf000015_0002
Figure imgf000015_0002
dans laquelle  in which
R15, R16, RI et R2 sont tels que définis précédemment, R5 représente un groupe -(CH2)P-NH2, avec p est égal à 2 ou 3, ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci. R15, R16, R1 and R2 are as defined previously, R5 is - (CH 2 ) p -NH 2 , where p is 2 or 3, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
Selon un mode de réalisation particulièrement préféré, la présente invention concerne un composé de formule (la) et de formule (le) tels que définies ci-dessus. On peut en particulier citer comme composés représentants de ce mode de réalisation particulier les composés (5) et (15) tels que définis ci-après. According to a particularly preferred embodiment, the present invention relates to a compound of formula (Ia) and of formula (Ic) as defined above. In particular, compounds representing this particular embodiment may be mentioned compounds (5) and (15) as defined below.
Selon un mode de réalisation préféré de la présente invention, un composé de formule (I) est choisi parmi : According to a preferred embodiment of the present invention, a compound of formula (I) is chosen from:
- (1) 3P-norspermino-N-isopropyl-désoxycholamide,  - (1) 3β-Norspermino-N-isopropyl-deoxycholamide,
- (2) 3P-norspermidino-N-isopropyl-désoxycholamide,  - (2) 3β-Norspermidino-N-isopropyl-deoxycholamide,
- (3) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide, - (3) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-deoxycholamide,
- (4) 3P-norspermino-N-isopropyl-cholamide, (4) 3β-Norspermino-N-isopropylcholamide,
- (5) 3P-norspermidino-N-isopropyl-cholamide,  - (5) 3β-Norspermidino-N-isopropylcholamide,
- (6) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide, (6) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-deoxycholamide,
- (7) 3 β-norspermino-N-isopropyl-chénodésoxycho lamide, - (7) 3β-norspermino-N-isopropyl-chenodeoxycholamide,
- (8) 3P-norspermidino-N-isopropyl-chénodésoxycholamide,  - (8) 3β-Norspermidino-N-isopropyl-chenodeoxycholamide,
- (9) 3P-(l,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl- chénodésoxycho lamide,  (9) 3 P- (1,4-bis (3-aminopropyl) piperazine) -N-isopropyl-chenodeoxycholamide,
- (10) 3P-norspermino-N-méthyl-chénodésoxycholamide,  - (10) 3β-Norspermino-N-methyl-chenodeoxycholamide,
- (11) 3 β-norspermidino-N-méthyl-chénodésoxycho lamide,  - (11) 3β-Norspermidino-N-methyl-chenodeoxycholamide,
- (12) 3P-(l,4-Bis(3-aminopropyl)pipérazine)-N-méthyl- chénodésoxycho lamide,  - (12) 3 P- (1,4-Bis (3-aminopropyl) piperazine) -N-methyl-chenodeoxycholamide,
- (13) 3P-norspermidino- N,N-diéthyl-chénodésoxycholamide,  (13) 3β-Norspermidino-N, N-diethyl-chenodeoxycholamide,
- (14) 3P-norspermino-N-isopropyl-ursodésoxycholamide,  - (14) 3β-Norspermino-N-isopropyl ursodeoxycholamide,
- (15) 3P-norspermidino-N-isopropyl-ursodésoxycholamide,  - (15) 3β-Norspermidino-N-isopropyl ursodeoxycholamide,
- (16) 3P-(l,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl- ursodésoxycho lamide,  (16) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-ursodeoxycholamide,
- (17) 3P-norspermino-N-isopropyl-lithocholamide, - (18) 3P-norspermidino-N-isopropyl-lithocholamide, - (17) 3 P-norspermino-N-isopropyl-lithocholamide, - (18) 3 P-norspermidino-N-isopropyl-lithocholamide,
- (19) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-lithocho lamide, (19) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-lithocholamide,
- (20) 3 P-(pentaéthylènehexamine)-N-isopropyl-désoxycho lamide,- (20) 3 P- (pentaethylenehexamine) -N-isopropyl-deoxycholamide,
- (21) 3P-(pentaéthylènehexamine)-N-isopropyl-cholamide, - (21) 3 P- (pentaethylenehexamine) -N-isopropylcholamide,
- (22) 3 P-(pentaéthylènehexamine)-N-isopropyl-chénodésoxycho lamide, (22) 3 P- (pentaethylenehexamine) -N-isopropyl-chenodeoxycholamide,
- (23) 3 P-(pentaéthylènehexamine)-N-isopropyl-ursodésoxycho lamide, (23) 3 P- (pentaethylenehexamine) -N-isopropyl ursodeoxycholamide,
- (24) N-isopropyl-3P-pentaéthylènehexamine-désoxycho lamide, - (24) N-isopropyl-3β-pentaethylenehexamine-deoxycholamide,
- (25) 3 β-( 1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycho lamide,(25) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-deoxycholamide,
- (26) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-cho lamide, - (27) 3P-(Bis(3-aminopropyl)méthylamine)-N-isopropyl- chénodésoxycho lamide, - (26) 3 P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-cholamide, - (27) 3 P- (bis (3-aminopropyl) methylamine) -N-isopropyl-chenodeoxycholamide,
- (28) 3P-(Bis(3-aminopropyl)méthylamine)-N-isopropyl- ursodésoxycho lamide,  - (28) 3 P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-ursodeoxycholamide,
- (29) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-lithocho lamide, - (30) 3 β-spermino-N-isopropyl-désoxycho lamide,  - (29) 3 P- (Bis (3-aminopropyl) methylamine) -N-isopropyl-lithocholamide, - (30) 3β-spermino-N-isopropyl-deoxycholamide,
- (31) 3P-spermino-N-isopropyl-cholamide,  - (31) 3β-spermino-N-isopropylcholamide,
- (32) 3P-spermino-N-isopropyl-chénodésoxycholamide,  - (32) 3β-Spermino-N-isopropyl-chenodeoxycholamide,
- (33) 3 β-spermino-N-méthyl-désoxycho lamide,  - (33) 3β-spermino-N-methyl-deoxycholamide,
- (34) 3P-spermino-N,N-diéthyl-chénodésoxycholamide,  - (34) 3β-spermino-N, N-diethyl-chenodeoxycholamide,
- (35) 3 β-spermino-N-isopropyl-ursodésoxycho lamide,  - (35) 3β-spermino-N-isopropyl ursodeoxycholamide,
- (36) 3P-spermino-N-isopropyl-lithocholamide,  - (36) 3β-spermino-N-isopropyl-lithocholamide,
- (37) 3P-norspermidino-N-diisopropyl-chénodésoxycholamide, - (37) 3β-Norspermidino-N-diisopropyl-chenodeoxycholamide,
- (38) 3P-norspermidino-N-cyclohexyl-chénodésoxycholamide,- (38) 3β-Norspermidino-N-cyclohexyl-chenodeoxycholamide,
- (39) 3P-norspermino-N,N-diéthyl-chénodésoxycholamide, - (39) 3β-Norspermino-N, N-diethyl-chenodeoxycholamide,
- (40) 3P-norspermino-N,N- diisopropyl-chénodésoxycholamide, - (40) 3β-Norspermino-N, N-diisopropyl-chenodeoxycholamide,
- (42) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-désoxycho lamide, (42) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl-deoxycholamide,
- (43) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-cho lamide,  (43) 3 P- (Tris (3-aminopropyl) amine) -N-isopropylcholamide,
- (44) 3 P-(Tris(3 -aminopropyl)amine)-N,N-diéthyl-chénodésoxycho lamide, - (44) 3 P- (Tris (3-aminopropyl) amine) -N, N-diethyl-chenodeoxycholamide,
- (45) 3 P-(Tris(2-amino éthyl)amine)-N-isopropyl-chénodésoxycho lamide, - (46) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-chénodésoxycho lamide,- (45) 3 P- (Tris (2-aminoethyl) amine) -N-isopropyl-chenodeoxycholamide, - (46) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl-chenodeoxycholamide,
- (47) 3P-(Tris(3-aminopropyl)amine)-N-cyclohexyl-chénodésoxycho lamide,(47) 3 P- (Tris (3-aminopropyl) amine) -N-cyclohexyl-chenodeoxycholamide,
- (48) 3P-(Tris(3-aminopropyl)amine)-N-isopropyl-ursodésoxycholamide, - (49) 3 P-(Tris(3 -aminopropyl)amine)-N-isopropyl-lithocho lamide, - (48) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl ursodeoxycholamide, - (49) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl-lithocholamide,
- (50) 3P-spermino-N,N-diisopropyl-chénodésoxycholamide,  - (50) 3β-spermino-N, N-diisopropyl-chenodeoxycholamide,
- (51) 3P-spermino-N-cyclohexyl-chénodésoxycholamide,  - (51) 3β-spermino-N-cyclohexyl-chenodeoxycholamide,
- (52) 3P-spermidino-N-isopropyl-chénodésoxycholamide,  - (52) 3β-spermidino-N-isopropyl-chenodeoxycholamide,
- (53) 3P-(Bis(3-aminopropyl)éthylènediamine)-N,N-diéthyl-chénodésoxy cho lamide,  (53) 3 P- (Bis (3-aminopropyl) ethylenediamine) -N, N-diethyl-chenodeoxycholamide,
- (54) 3P-(Bis(3-aminopropyl)éthylènediamine)-N,N-diisopropyl-chénodésoxy cho lamide,  (54) 3 P- (Bis (3-aminopropyl) ethylenediamine) -N, N-diisopropyl-chenodeoxycholamide,
- (55) Mélange 50/50 de 3P-spermidino-N-isopropyl-chénodésoxycholamide et de 3P-N-[4'N-(3'-aminopropyl)aminobutyl]amino-N-isopropyl-chénodésoxycho lamide,  (55) 50/50 mixture of 3β-spermidino-N-isopropyl-chenodeoxycholamide and 3β-N- [4'N- (3'-aminopropyl) aminobutyl] amino-N-isopropyl-chenodeoxycholamide,
- (56) 3P-(Tris(3-aminopropyl)amine)-N,N- diisopropyl-chénodésoxy cho lamide,  (56) 3 P- (Tris (3-aminopropyl) amine) -N, N-diisopropyl-chenodeoxycholamide,
ou l'un de ses sels pharmaceutiquement acceptables.  or a pharmaceutically acceptable salt thereof.
Les composés de l'invention peuvent exister sous forme de bases libres ou de sels d'addition à des acides pharmaceutiquement acceptables. The compounds of the invention may exist as free bases or addition salts with pharmaceutically acceptable acids.
Selon un mode de réalisation particulier de l'invention, de tels sels d'addition d'acides pharmaceutiquement acceptables comprennent le bromhydrate, le tartrate, le citrate, le trifluoroacétate, l'ascorbate, le chlorhydrate, le triflate, le maléate, le mesylate, le formate, l'acétate et le fumarate, et plus particulièrement le chlorhydrate.  According to a particular embodiment of the invention, such pharmaceutically acceptable acid addition salts include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, maleate, mesylate. formate, acetate and fumarate, and more particularly the hydrochloride.
Les composés de formule (I), (F), (la), (Ib), (le), (Id) et (le) ainsi que les composés (1) à (56) peuvent se présenter sous forme de solvates tels que des hydrates. L'invention comprend ces solvates.  The compounds of formula (I), (F), (Ia), (Ib), (Ie), (Id) and (Ie) as well as the compounds (1) to (56) may be in the form of solvates such as than hydrates. The invention includes these solvates.
Un composé de formule (I), (Γ), (la), (Ib), (le), (Id) ou (le) peut comprendre un ou plusieurs atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantio mères ou de diastéréoisomères. Ces énantio mères, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques, sont inclus dans la portée de la présente invention. D'une manière générale, dans le cadre de la présente invention, lorsqu'une liaison est représentée par le symbole ~~ΛΛΛ/ , cela signifie que le groupe porté par le carbone considéré peut-être en arrière ou en avant du plan de représentation de la molécule. Ainsi, la stéréochimie résultante du carbone portant ce groupe peut être S ou R. A compound of formula (I), (Γ), (Ia), (Ib), (Ie), (Id) or (Ie) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, are included within the scope of the present invention. In a general manner, in the context of the present invention, when a link is represented by the symbol ~ ~ ΛΛΛ / , this means that the group carried by the carbon considered perhaps behind or in front of the representation plane of the molecule. Thus, the resulting stereochemistry of carbon bearing this group may be S or R.
Selon un autre aspect, la présente invention concerne un composé de formule (I), (F), (la), (Ib), (le), (Id) ou (le) ou encore un composé (1) à (56) ou l'un de ses sels pharmaceutiquement acceptable, pour son utilisation à titre de médicament.  According to another aspect, the present invention relates to a compound of formula (I), (F), (Ia), (Ib), (Ie), (Id) or (Ie) or a compound (1) to (56) or a pharmaceutically acceptable salt thereof for use as a medicament.
Selon un autre aspect, la présente invention concerne un composé de formule (I), (Γ), (la), (Ib), (le), (Id) ou (le) pour son utilisation pour prévenir et/ou inhiber et/ou traiter les infections bactériennes, fongiques, virales ou parasitaires chez l'homme ou l'animal.  According to another aspect, the present invention relates to a compound of formula (I), (Γ), (Ia), (Ib), (Ie), (Id) or (Ie) for its use for preventing and / or inhibiting and or treat bacterial, fungal, viral or parasitic infections in humans or animals.
Selon la présente invention, le terme «prévenir» ou «prévention» signifie que pour réduire le risque d'apparition ou de ralentir l'apparition d'un phénomène donné, à savoir une infection bactérienne, fongique, virale ou parasitaire.  According to the present invention, the term "prevent" or "prevent" means that to reduce the risk of occurrence or slow down the occurrence of a given phenomenon, namely a bacterial, fungal, viral or parasitic infection.
Les composés de la présente invention peuvent être préparés par des procédés classiques de synthèse organique pratiquée par l'homme du métier. Le schéma général de réaction décrit ci-dessous représente une méthode générale utile pour préparer les composés de la présente invention et n'est pas destiné à en limiter la portée ou l'utilité. The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction scheme described below represents a general useful method for preparing the compounds of the present invention and is not intended to limit its scope or utility.
Ainsi, les composés de l'invention peuvent être préparés par application ou adaptation de toute méthode connue en soi de et/ou à la portée de l'homme du métier, notamment celles décrites par Larock dans Comprehensive Organic Transformations, VCH Pub., 1989, ou par application ou adaptation des procédés décrits dans les exemples qui suivent.  Thus, the compounds of the invention may be prepared by application or adaptation of any method known per se and / or within the scope of those skilled in the art, in particular those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989 or by application or adaptation of the methods described in the examples which follow.
Selon un mode de réalisation particulier, les composés de l'invention peuvent être préparés selon le schéma de synthèse 1 ci-dessous. According to a particular embodiment, the compounds of the invention may be prepared according to Synthetic Scheme 1 below.
Schéma 1 Diagram 1
Figure imgf000020_0001
Figure imgf000020_0001
(Π)  (Π)
Selon ce schéma 1, un composé de formule (IV), dans laquelle RI et R2 sont tels que définis précédemment, est mis à réagir, dans un solvant tel que CH2CI2, THF, dioxane, par exemple en présence d'agent de couplage tel que HOBT/DCC, BOP, chloroformiate de méthyle avec un composé de formule R15R16NH, dans laquelle R15 et RI 6 sont tels que définis précédemment, par exemple à une température comprise entre - 20°C et 20°C, pour obtenir un composé de formule (III).  According to this scheme 1, a compound of formula (IV), in which R 1 and R 2 are as defined above, is reacted in a solvent such as CH 2 Cl 2, THF or dioxane, for example in the presence of a coupling agent such as that HOBT / DCC, BOP, methyl chloroformate with a compound of formula R15R16NH, wherein R15 and RI6 are as defined above, for example at a temperature between -20 ° C and 20 ° C, to obtain a compound of formula (III).
Toujours selon ce schéma 1, le composé de formule (III) ainsi obtenu est soumis à une oxydation en présence d'un ligand, par exemple du tri-tert-butylate d'aluminium, tri-isopropylate d'aluminium ou Ag2C03, dans un solvant tel que par exemple le benzène, le toluène, le cyclohexane ou le trifluorotoluène, par exemple à une température comprise entre 20°C et 100°C, pour obtenir un composé de formule (II). According to this scheme 1, the compound of formula (III) thus obtained is subjected to oxidation in the presence of a ligand, for example tri-tert-butoxide, aluminum tri-isopropoxide or Ag2C0 3 a solvent such as for example benzene, toluene, cyclohexane or trifluorotoluene, for example at a temperature between 20 ° C and 100 ° C, to obtain a compound of formula (II).
Toujours selon ce schéma 1 , le composé de formule (II) ainsi obtenu est soumis à une amination réductrice par réaction avec un composé de formule R'NH2, dans laquelle R' est tel que défini précédemment, en présence d'un agent réducteur tel que le tétraisopropylate de titane, le tétraisopropylate de zirconium, le NaBH3CN, le NaBH4, ou d'un mélange d'entre eux, préférentiellement le couple tétraisopropylate de titane/NaBH4, par exemple à une température comprise entre -120°C et -10°C, préférentiellement -80°C et -10°C, pour obtenir le composé de formule (I). Eventuellement ledit procédé peut également comprendre l'étape consistant à isoler le produit obtenu. Still according to this scheme 1, the compound of formula (II) thus obtained is subjected to reductive amination by reaction with a compound of formula R'NH2, in which R 'is as defined above, in the presence of a reducing agent such as titanium tetraisopropylate, zirconium tetraisopropylate, NaBH 3 CN, NaBH 4 , or a mixture of them, preferably the tetraisopropylate pair of titanium / NaBH 4 , for example at a temperature between -120 ° C and -10 ° C, preferably -80 ° C and -10 ° C, to obtain the compound of formula (I). Optionally, said method may also comprise the step of isolating the product obtained.
Le composé ainsi préparé peut être récupéré à partir du mélange de la réaction par les moyens traditionnels. Par exemple, les composés peuvent être récupérés en distillant le solvant du mélange de la réaction ou si nécessaire après distillation du solvant du mélange de la solution, en versant le reste dans de l'eau suivi par une extraction avec un solvant organique immiscible dans l'eau, et en distillant le solvant de l'extrait. En outre, le produit peut, si on le souhaite, être encore purifié par diverses techniques, telles que la recristallisation, la reprécipitation ou les diverses techniques de chromatographie, notamment la chromatographie sur colonne ou la chromatographie en couche mince préparative.  The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or if necessary after distilling the solvent from the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in the reaction mixture. water, and distilling the solvent from the extract. In addition, the product may, if desired, be further purified by various techniques, such as recrystallization, reprecipitation or various chromatography techniques, including column chromatography or preparative thin layer chromatography.
Le composé de départ de formule (IV) est disponible ou peut être préparé selon les méthodes connues de l'homme de l'art et/ou peuvent être préparés par l'application des procédés tels que décrits dans les Exemples ou leurs équivalents chimiques évidents. The starting compound of formula (IV) is available or may be prepared according to methods known to those skilled in the art and / or may be prepared by the application of the methods as described in the Examples or their obvious chemical equivalents .
Selon une variante préférée, les composés de formule (I) sont synthétisés à partir des composés de formule (IV), tels que définis ci-dessus ou acides biliaires suivants : According to a preferred variant, the compounds of formula (I) are synthesized from the compounds of formula (IV), as defined above or bile acids:
Figure imgf000022_0001
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000022_0003
acide lithocholique  lithocholic acid
Ainsi, selon un autre objet, la présente invention concerne également le procédé de préparation des composés de formule (I) précédemment décrits, comprenant une étape d'amination réductrice du composé de formule (II)  Thus, according to another object, the present invention also relates to the process for the preparation of the compounds of formula (I) described above, comprising a step of reductive amination of the compound of formula (II)
Figure imgf000022_0004
Figure imgf000022_0004
dans laquelle R15, R16, RI et R2 sont tels que définis précédemment, avec une aminé de formule R'NH2, dans laquelle R' est telle que définie précédemment, en présence d'un agent réducteur pouvant être choisi parmi le tétraisopropylate de titane, le tétraisopropylate de zirconium, le NaBH3CN, le NaBH4, ou d'un mélange d'entre eux, préférentiellement le couple tétraisopropylate de titane/NaBH4, pour obtenir ledit composé de formule (I). in which R15, R16, R1 and R2 are as defined above, with an amine of formula R'NH2, in which R 'is as defined above, in the presence of a reducing agent that may be chosen from titanium tetraisopropylate, zirconium tetraisopropylate, NaBH 3 CN, NaBH 4 , or a mixture of them, preferably the tetraisopropylate pair of titanium / NaBH 4 , to obtain said compound of formula (I).
Les structures chimiques et les données spectroscopiques de quelques composés de formule (I) de l'invention sont illustrées respectivement dans le tableau I et le tableau II suivant. The chemical structures and the spectroscopic data of some compounds of formula (I) of the invention are illustrated respectively in Table I and the following Table II.
Table I  Table I
Figure imgf000023_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
L'invention couvre également un mélange 50/50 de 3P-spermidino-N- isopropyl-chénodésoxycholamide et de 3P-N-[4'N-(3'-aminopropyl)aminobutyl]amino-N- isopropyl-chénodésoxycholamide nommé composé (55) dans la description qui va suivre The invention also covers a 50/50 mixture of 3β-spermidino-N-isopropyl-chenodeoxycholamide and 3β-N- [4'N- (3'-aminopropyl) aminobutyl] amino-N-isopropyl-chenodeoxycholamide named compound (55 ) in the following description
Figure imgf000027_0002
Tableau II
Figure imgf000027_0002
Table II
Les structures chimiques synthétisées ont toutes été vérifiées par une analyse RMN du proton (!H) et/ou du carbone (13C) dans du chloroforme deutéré CDCI3 ou du méthanol deutéré CD3OD sur un appareil de type Bruker AC 300. Les déplacements chimiques δ sont exprimés en ppm. Les fréquences d'enregistrements des noyaux ainsi que des références utilisées sont les suivantes : The synthesized chemical structures were all verified by proton NMR analysis ( ! H) and / or carbon ( 13 C) in deuterated chloroform CDCl3 or deuterated methanol CD3OD on a Bruker AC 300 type apparatus. The chemical shifts δ are expressed in ppm. The recording frequencies of the cores and the references used are as follows:
RMN du Ή : 300 MHz, Si(CH3)4 RM NMR: 300 MHz, Si (CH 3 ) 4
RMN du 13C : 75 MHz, Si(CH3)4 13 C NMR: 75 MHz, Si (CH 3 ) 4
Les abréviations utilisées pour l'écriture du spectre JH sont les suivantes :The abbreviations used for writing the spectrum J H are as follows:
- s = singulet - s = singlet
- d = doublet  - d = doublet
- 1 = triplet  - 1 = triplet
- q = quadruplet  - q = quadruplet
- m = massif  - m = massive
Ex Caractérisation Ex Characterization
1 RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 2H), 2.71-2.59 (m, 13H), 2.21-0.70 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.19, 59.07, 49.31, 49.00, 48.24, 47.74, 45.85, 44.08, 42.41, 40.78, 37.59, 37.12, 37.01, 35.95, 35.92, 34.94, 34.58, 34.36, 33.56, 30.50, 30.30, 29.98, 28.84, 28.64, 28.27, 27.64, 25.04, 24.08, 22.82, 22.76, 17.85, 13.35 ¹H NMR (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 2H), 2.71-2.59 (m, 13H), 2.21-0.70 (m, 54H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.93, 74.19, 59.07, 49.31, 49.00, 48.24, 47.74, 45.85, 44.08, 42.41, 40.78, 37.59, 37.12, 37.01, 35.95, 35.92, 34.94, 34.58 , 34.36, 33.56, 30.50, 30.30, 29.98, 28.84, 28.64, 28.27, 27.64, 25.04, 24.08, 22.82, 22.76, 17.85, 13.35
2 RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.89 (m, 2H), 2.72-2.51 (m, 9H), 2.25-0.70 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.55, 72.85, 59.06, 49.33, 49.06, 48.42, 48.25, 47.76, 45.84, 44.06, 42.41, 40.75, 37.58, 37.10, 37.01, 35.91, 34.95, 34.47, 34.37, 33.55, 33.34, 30.33, 29.98, 28.84, 28.62, 28.19, 27.64, 25.04, 24.07, 22.82, 22.76, 17.84, 13.35 2 RM NMR (250 MHz, CD3OD): δ (ppm) = 3.99-3.89 (m, 2H), 2.72-2.51 (m, 9H), 2.25-0.70 (m, 51H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.55, 72.85, 59.06, 49.33, 49.06, 48.42, 48.25, 47.76, 45.84, 44.06, 42.41, 40.75, 37.58, 37.10, 37.01, 35.91, 34.95, 34.47 , 34.37, 33.55, 33.34, 30.33, 29.98, 28.84, 28.62, 28.19, 27.64, 25.04, 24.07, 22.82, 22.76, 17.84, 13.35
3 RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.89 (m, 2H), 2.69-2.38 (m, 17H), 2.27-0.70 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 74.13, 59.06, 58.03, 57.50, 54.10, 54.03, 49.30, 48.21, 47.75, 46.29, 44.04, 42.38, 41.16, 37.58, 37.01, 35.92, 34.92, 34.64, 34.35, 33.53, 30.55, 30.00, 28.85, 28.65, 28.34, 27.65, 27.42, 25.06, 24.12, 22.85, 22.79, 17.87, 13.38 RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.96-3.95 (m, 2H), 3.80(m, 1H), 2.76-2.69 (m, 13H), 2.54-0.72 (m, 53H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 74.01, 69.00, 59.32, 57.39, 54.01, 48.21, 47.64, 45.53, 43.55, 43.13, 42.39, 41.16, 41.00, 40.54, 37.07, 36.92, 36.73, 36.38, 35.98, 34.43, 33.56, 32.12, 29.65, 28.89, 28.02, 27.45, 24.38, 23.44, 22.84, 22.78, 17.93, 13.16 3 RM NMR (250 MHz, CD3OD): δ (ppm) = 3.99-3.89 (m, 2H), 2.69-2.38 (m, 17H), 2.27-0.70 (m, 50H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.87, 74.13, 59.06, 58.03, 57.50, 54.10, 54.03, 49.30, 48.21, 47.75, 46.29, 44.04, 42.38, 41.16, 37.58, 37.01, 35.92, 34.92 , 34.64, 34.35, 33.53, 30.55, 30.00, 28.85, 28.65, 28.34, 27.65, 27.42, 25.06, 24.12, 22.85, 22.79, 17.87, 13.38 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.96-3.95 (m, 2H), 3.80 (m, 1H), 2.76-2.69 (m, 13H), 2.54-0.72 (m, 53H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.88, 74.01, 69.00, 59.32, 57.39, 54.01, 48.21, 47.64, 45.53, 43.55, 43.13, 42.39, 41.16, 41.00, 40.54, 37.07, 36.92, 36.73 , 36.38, 35.98, 34.43, 33.56, 32.12, 29.65, 28.89, 28.02, 27.45, 24.38, 23.44, 22.84, 22.78, 17.93, 13.16
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.97-3.94 (m, 2H), 3.80 (m, 1H), 2.90-2.59 (m, 9H), 2.29-0.71 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.91, 74.00, 68.98, 59.23, 49.00, 48.22, 47.62, 45.64, 43.42, 43.19, 42.40, 41.15, 40.42, 37.07, 36.74, 36.30, 35.89, 34.43, 33.56, 31.66, 29.69, 28.87, 28.32, 28.05, 27.14, 24.34, 23.36, 22.82, 22.76, 17.90, 13.15 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.97-3.94 (m, 2H), 3.80 (m, 1H), 2.90-2.59 (m, 9H), 2.29-0.71 (m, 50H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.91, 74.00, 68.98, 59.23, 49.00, 48.22, 47.62, 45.64, 43.42, 43.19, 42.40, 41.15, 40.42, 37.07, 36.74, 36.30, 35.89, 34.43 , 33.56, 31.66, 29.69, 28.87, 28.32, 28.05, 27.14, 24.34, 23.36, 22.82, 22.76, 17.90, 13.15
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 2H), 3.79(m, 1H), 2.76-2.39 (m, 23H), 2.28-0.71 (m, 43H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.03, 69.03, 59.34, 57.97, 57.44, 54.10, 54.02, 47.66, 46.24, 46.08, 43.65, 43.14, 42.41, 41.21, 41.09, 37.28, 37.07, 36.42, 36.02, 34.43, 33.56, 30.11, 29.74, 28.87, 28.06, 27.92, 26.67, 24.38, 23.48, 22.83, 22.76, 17.91, 13.16 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 2H), 3.79 (m, 1H), 2.76-2.39 (m, 23H), 2.28-0.71 (m, 43H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.93, 74.03, 69.03, 59.34, 57.97, 57.44, 54.10, 54.02, 47.66, 46.24, 46.08, 43.65, 43.14, 42.41, 41.21, 41.09, 37.28, 37.07 , 36.42, 36.02, 34.43, 33.56, 30.11, 29.74, 28.87, 28.06, 27.92, 26.67, 24.38, 23.48, 22.83, 22.76, 17.91, 13.16
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.92- 2.74 (m, 13H), 2.20-0.69 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 68.97, 59.31, 57.60, 51.74, 48.54, 45.26, 43.83, 43.42, 42.43, 41.21, 40.91, 40.32, 37.06, 36.65, 36.06, 35.88, 34.40, 34.21, 33.56, 30.84, 29.44, 29.04, 27.99, 27.01, 24.74, 23.55, 22.81, 22.73, 21.91, 19.07, 12.33 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.92- 2.74 (m, 13H), 2.20-0.69 (m, 54H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.88, 68.97, 59.31, 57.60, 51.74, 48.54, 45.26, 43.83, 43.42, 42.43, 41.21, 40.91, 40.32, 37.06, 36.65, 36.06, 35.88, 34.40 , 34.21, 33.56, 30.84, 29.44, 29.04, 27.99, 27.01, 24.74, 23.55, 22.81, 22.73, 21.91, 19.07, 12.33
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.95 (m, 1H), 3.80 (m, 1H), 2.75- 2.63 (m, 9H), 2.27-0.70 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.82, 69.03, 59.40, 57.51, 51.69, 48.94, 48.28, 45.64, 43.82, 43.61, 42.41, 41.20, 40.94, 40.63, 37.05, 36.76, 36.03, 34.36, 34.19, 33.55, 32.81, 29.57, 29.45, 28.01, 24.77, 23.72, 22.83, 22.76, 21.91, 19.11, 12.37 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.95 (m, 1H), 3.80 (m, 1H), 2.75- 2.63 (m, 9H), 2.27-0.70 (m, 51H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.82, 69.03, 59.40, 57.51, 51.69, 48.94, 48.28, 45.64, 43.82, 43.61, 42.41, 41.20, 40.94, 40.63, 37.05, 36.76, 36.03, 34.36 , 34.19, 33.55, 32.81, 29.57, 29.45, 28.01, 24.77, 23.72, 22.83, 22.76, 21.91, 19.11, 12.37
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.81 (m, 1H), 3.09- 2.82 (m, 17H), 2.20-0.70 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 68.81, 59.37, 57.67, 55.76, 52.43, 52.27, 52.16, 52.09, 51.82, 51.99, 43.83, 43.09, 42.44, 41.24, 40.90, 40.75, 37.07, 36.67, 36.46, 34.43, 34.24, 34.16, 33.56, 30.91, 30.89, 29.46, 25.36, 24.74, 23.55, 22.80, 22.73, 19.08, 12.33 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.81 (m, 1H), 3.09-2.82 (m, 17H), 2.20-0.70 (m, 50H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.88, 68.81, 59.37, 57.67, 55.76, 52.43, 52.27, 52.16, 52.09, 51.82, 51.99, 43.83, 43.09, 42.44, 41.24, 40.90, 40.75, 37.07 , 36.67, 36.46, 34.43, 34.24, 34.16, 33.56, 30.91, 30.89, 29.46, 25.36, 24.74, 23.55, 22.80, 22.73, 19.08, 12.33
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.73-2.61 (m, 13H), 2.24-0.69 (m, 48H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.40, 69.03, 59.45, 57.44, 52.18, 51.67, 48.95, 48.43, 45.73, 43.81, 43.69, 41.20, 40.96, 40.72, 37.57, 37.21, 36.80, 36.10, 34.18, 33.21, 32.39, 31.97, 30.13, 30.02, 29.41, 28.29, 24.79, 23.79, 21.95, 19.00, 12.42 NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.73-2.61 (m, 13H), 2.24-0.69 (m, 48H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 176.40, 69.03, 59.45, 57.44, 52.18, 51.67, 48.95, 48.43, 45.73, 43.81, 43.69, 41.20, 40.96, 40.72, 37.57, 37.21, 36.80, 36.10 , 34.18, 33.21, 32.39, 31.97, 30.13, 30.02, 29.41, 28.29, 24.79, 23.79, 21.95, 19.00, 12.42
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.72-2.63 (m, 9H), 2.44-0.69 (m, 45H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.38, 68.95, 59.31, 57.34, 52.02, 51.57, 48.86, 48.19, 45.55, 43.70, 43.54, 41.10, 40.85, 40.55, 37.00, 36.79, 36.67, 35.93, 34.09, 32.77, 32.28, 31.87, 29.57, 29.29, 27.97, 24.67, 23.63, 21.83, 18.87, 12.28 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.72-2.63 (m, 9H), 2.44-0.69 (m, 45H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 176.38, 68.95, 59.31, 57.34, 52.02, 51.57, 48.86, 48.19, 45.55, 43.70, 43.54, 41.10, 40.85, 40.55, 37.00, 36.79, 36.67, 35.93 , 34.09, 32.77, 32.28, 31.87, 29.57, 29.29, 27.97, 24.67, 23.63, 21.83, 18.87, 12.28
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.71-0.42 (m, 17H), 2.32-0.70 (m, 44H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.46, 69.03, 59.36, 58.05, 57.47, 54.13, 53.99, 52.18, 51.69, 46.18, 43.82, 43.66, 41.22, 41.12, 40.97, 37.58, 37.18, 37.18, 36.90, 36.79, 36.07, 34.21, 32.39, 31.97, 30.35, 29.40, 28.36, 26.93, 24.77, 23.75, 21.93, 18.98, 12.40 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.71-0.42 (m, 17H), 2.32-0.70 (m, 44H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 176.46, 69.03, 59.36, 58.05, 57.47, 54.13, 53.99, 52.18, 51.69, 46.18, 43.82, 43.66, 41.22, 41.12, 40.97, 37.58, 37.18, 37.18 , 36.90, 36.79, 36.07, 34.21, 32.39, 31.97, 30.35, 29.40, 28.36, 26.93, 24.77, 23.75, 21.93, 18.98, 12.40
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.72- 2.59 (m, 8H), 2.38-0.70 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.42, 69.07, 59.48, 57.47, 51.66, 49.08, 48.42, 45.79, 43.83, 43.74, 41.62, 41.21, 40.98, 40.79, 37.86, 37.30, 37.18, 36.83, 36.11, 34.18, 33.58, 33.23, 31.15, 30.41, 29.48, 28.54, 24.80, 23.82, 21.94, 19.25, 14.84, 13.47, 12.42 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.72- 2.59 (m, 8H), 2.38-0.70 (m, 51H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.42, 69.07, 59.48, 57.47, 51.66, 49.08, 48.42, 45.79, 43.83, 43.74, 41.62, 41.21, 40.98, 40.79, 37.86, 37.30, 37.18, 36.83 ,,,,,
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.46 (m, 1H), 2.89- 2.65 (m, 13H), 2.54-0.71 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 72.04, 58.88, 57.64, 56.75, 48.31, 46.72, 45.74, 44.94, 44.66, 44.46, 42.42, 41.70, 40.80, 40.56, 38.82, 36.97, 36.68, 35.85, 35.75, 34.97, 34.40, 33.60, 32.19, 29.84, 29.71, 29.66, 28.10, 24.25, 22.81, 22.76, 22.54, 19.22, 12.80 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.46 (m, 1H), 2.89- 2.65 (m, 13H), 2.54-0.71 (m, 54H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.87, 72.04, 58.88, 57.64, 56.75, 48.31, 46.72, 45.74, 44.94, 44.66, 44.46, 42.42, 41.70, 40.80, 40.56, 38.82, 36.97, 36.68 , 35.85, 35.75, 34.97, 34.40, 33.60, 32.19, 29.84, 29.71, 29.66, 28.10, 24.25, 22.81, 22.76, 22.54, 19.22, 12.80
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.85- 2.49 (m, 9H), 2.24-0.71 (m, 51H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 72.06, 58.89, 57.65, 56.74, 48.94, 48.39, 45.85, 44.95, 44.67, 44.50, 42.42, 41.72, 40.81, 40.70, 38.87, 36.97, 36.75, 35.86, 35.78, 35.25, 34.39, 33.60, 33.06, 30.26, 29.84, 28.10, 24.28, 22.81, 22.76, 22.54, 19.23, 12.80 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.85- 2.49 (m, 9H), 2.24-0.71 (m, 51H). 13 C NMR (63 MHz, CD 3 OD): δ (ppm) = 175.87, 72.06, 58.89, 57.65, 56.74, 48.94, 48.39, 45.85, 44.95, 44.67, 44.50, 42.42, 41.72, 40.81, 40.70, 38.87, 36.97, 36.75, 35.86, 35.78, 35.25, 34.39, 33.60, 33.06, 30.26, 29.84, 28.10, 24.28, 22.81, 22.76, 22.54, 19.23, 12.80
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.70- 2.38 (m, 17H), 2.20-0.71 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.74, 72.01, 58.86, 58.05, 57.67, 56.74, 54.13, 54.03, 46.41, 44.94, 44.65,NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.70- 2.38 (m, 17H), 2.20-0.71 (m, 50H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.74, 72.01, 58.86, 58.05, 57.67, 56.74, 54.13, 54.03, 46.41, 44.94, 44.65,
44.48, 44.39, 42.38, 41.73, 41.16, 40.81, 38.93, 36.97, 36.80, 35.89, 35.78,44.48, 44.39, 42.38, 41.73, 41.16, 40.81, 38.93, 36.97, 36.80, 35.89, 35.78,
35.49, 34.39, 33.59, 30.51, 29.87, 28.33, 28.11, 27.37, 24.37, 22.87, 22.81, 22.56, 19.29, 12.87 35.49, 34.39, 33.59, 30.51, 29.87, 28.33, 28.11, 27.37, 24.37, 22.87, 22.81, 22.56, 19.29, 12.87
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.96-2.77 (m, 13H), 2.52-0.69 (m, 55H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.89, 59.07, 58.00, 57.69, 47.93, 44.06, 42.44, 41.91, 41.59, 39.96, 37.29, 36.99, 36.03, 34.40, 33.53, 29.42, 29.01, 28.75, 28.24, 26.01, 25.37, 23.96, 23.93, 22.79, 22.73, 22.07, 19.03, 12.61 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 2.96-2.77 (m, 13H), 2.52-0.69 (m, 55H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.89, 59.07, 58.00, 57.69, 47.93, 44.06, 42.44, 41.91, 41.59, 39.96, 37.29, 36.99, 36.03, 34.40, 33.53, 29.42, 29.01, 28.75 , 28.24, 26.01, 25.37, 23.96, 23.93, 22.79, 22.73, 22.07, 19.03, 12.61
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.74-2.62 (m, 9H), 2.25-0.69 (m, 52H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.86, 59.04, 58.06, 57.63, 48.92, 48.37, 45.83, 44.07, 43.92, 42.43, 41.97, 41.67, 40.67, 37.37, 37.05, 36.98, 36.26, 34.35, 33.52, 32.90, 30.02, 29.44, 28.55, 28.11, 27.80, 25.42, 24.28, 22.81, 22.75, 22.11, 19.06, 12.65 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 2.74-2.62 (m, 9H), 2.25-0.69 (m, 52H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.86, 59.04, 58.06, 57.63, 48.92, 48.37, 45.83, 44.07, 43.92, 42.43, 41.97, 41.67, 40.67, 37.37, 37.05, 36.98, 36.26, 34.35 , 33.52, 32.90, 30.02, 29.44, 28.55, 28.11, 27.80, 25.42, 24.28, 22.81, 22.75, 22.11, 19.06, 12.65
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.72-2.39 (m, 15H), 2.23-0.96 (m, 53H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 59.01, 58.12, 58.02, 57.66, 57.50, 54.14, 54.02, 46.36, 44.09, 43.90, 42.43, 42.00, 41.69, 41.09, 37.37, 37.06, 36.99, 36.27, 34.40, 34.35, 33.53, 30.17, 29.44, 28.55, 28.28, 27.83, 27.12, 25.42, 24.28, 22.81, 22.75, 22.11, 19.05, 12.65 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 2.72-2.39 (m, 15H), 2.23-0.96 (m, 53H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.88, 59.01, 58.12, 58.02, 57.66, 57.50, 54.14, 54.02, 46.36, 44.09, 43.90, 42.43, 42.00, 41.69, 41.09, 37.37, 37.06, 36.99 , 36.27, 34.40, 34.35, 33.53, 30.17, 29.44, 28.55, 28.28, 27.83, 27.12, 25.42, 24.28, 22.81, 22.75, 22.11, 19.05, 12.65
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.89 (m, 2H), 2.85-2.54 (m, 21H), 2.27-0.70 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 74.06, 59.10, 57.27, 55.25, 55.05, 54.99, 54.27, 54.18, 49.31, 48.23, 47.74,NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.99-3.89 (m, 2H), 2.85-2.54 (m, 21H), 2.27-0.70 (m, 50H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.87, 74.06, 59.10, 57.27, 55.25, 55.05, 54.99, 54.27, 54.18, 49.31, 48.23, 47.74,
46.97, 46.32, 46.18, 43.95, 42.38, 37.55, 36.99, 35.84, 34.94, 34.39, 33.52,46.97, 46.32, 46.18, 43.95, 42.38, 37.55, 36.99, 35.84, 34.94, 34.39, 33.52,
29.98, 28.84, 28.55, 27.60, 25.02, 24.02, 22.84, 22.78, 22.27, 17.86, 13.37 29.98, 28.84, 28.55, 27.60, 25.02, 24.02, 22.84, 22.78, 22.27, 17.86, 13.37
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.96-3.91 (m, 2H), 3.79 (m, 1H), 2.85-2.46 (m, 24H), 2.24-0.93 (m, 43H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.95, 74.10, 69.11, 59.54, 55.35, 54.48, 54.27, 54.07, 49.68, 48.19, 47.66, 47.07, 46.21, 43.73, 43.11, 42.41, 41.89, 41.21, 39.08, 37.77, 37.14, 37.06, 36.48, 36.06, 34.40, 33.55, 29.70, 28.87, 28.34, 28.04, 24.38, 23.52, 22.82, 22.76, 17.91, 13.15 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.96-3.91 (m, 2H), 3.79 (m, 1H), 2.85-2.46 (m, 24H), 2.24-0.93 (m, 43H), 0.71 ( s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.95, 74.10, 69.11, 59.54, 55.35, 54.48, 54.27, 54.07, 49.68, 48.19, 47.66, 47.07, 46.21, 43.73, 43.11, 42.41, 41.89, 41.21, 39.08, 37.77, 37.14, 37.06, 36.48, 36.06, 34.40, 33.55, 29.70, 28.87, 28.34, 28.04, 24.38, 23.52, 22.82, 22.76, 17.91, 13.15
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.85- 2.43 (m, 23H), 2.37-0.69 (m, 48H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 69.10, 59.59, 58.60, 57.52, 55.37, 54.48, 54.28, 54.08, 51.70, 43.84, 42.42, 41.92, 41.23, 40.97, 39.11, 37.23, 37.05, 36.82, 36.10, 34.37, 34.21, 33.56, 29.44, 28.64, 28.59, 24.78, 23.76, 22.83, 22.76, 21.94, 19.10, 12.36 NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.85- 2.43 (m, 23H), 2.37-0.69 (m, 48H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.87, 69.10, 59.59, 58.60, 57.52, 55.37, 54.48, 54.28, 54.08, 51.70, 43.84, 42.42, 41.92, 41.23, 40.97, 39.11, 37.23, 37.05 , 36.82, 36.10, 34.37, 34.21, 33.56, 29.44, 28.64, 28.59, 24.78, 23.76, 22.83, 22.76, 21.94, 19.10, 12.36
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.84- 2.46 (m, 22H), 2.26-0.71 (m, 49H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.81, 72.04, 57.68, 56.74, 54.29, 54.26, 49.93, 47.10, 46.93, 46.37, 46.23, 44.94, 44.66, 44.50, 42.41, 41.93, 41.73, 40.83, 39.12, 38.90, 36.97, 36.77, 35.78, 34.39, 33.59, 29.85, 28.41, 28.10, 24.33, 22.84, 22.78, 22.54, 19.25, 12.83 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.84- 2.46 (m, 22H), 2.26-0.71 (m, 49H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.81, 72.04, 57.68, 56.74, 54.29, 54.26, 49.93, 47.10, 46.93, 46.37, 46.23, 44.94, 44.66, 44.50, 42.41, 41.93, 41.73, 40.83 , 39.12, 38.90, 36.97, 36.77, 35.78, 34.39, 33.59, 29.85, 28.41, 28.10, 24.33, 22.84, 22.78, 22.54, 19.25, 12.83
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.95 (m, 1H), 2.84-2.53 (m, 22H), 2.27-0.69 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.80, 58.07, 57.63, 54.28, 52.23, 44.06, 43.91, 42.41, 41.99, 41.81, 41.67, 37.37, 36.97, 36.27, 34.39, 34.34, 33.51, 29.43, 28.58, 28.42, 28.32, 27.83, 25.44, 24.33, 22.84, 22.78, 22.11, 19.09, 12.69 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.95 (m, 1H), 2.84-2.53 (m, 22H), 2.27-0.69 (m, 50H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.80, 58.07, 57.63, 54.28, 52.23, 44.06, 43.91, 42.41, 41.99, 41.81, 41.67, 37.37, 36.97, 36.27, 34.39, 34.34, 33.51, 29.43 , 28.58, 28.42, 28.32, 27.83, 25.44, 24.33, 22.84, 22.78, 22.11, 19.09, 12.69
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.99-3.91 (m, 2H), 2.68-0.70 (m, 62H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.84, 74.13, 59.10, 57.14, 56.62, 56.57, 49.29, 47.69, 46.19, 44.06, 42.47, 42.37, 41.13, 37.58, 36.99,NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.99-3.91 (m, 2H), 2.68-0.70 (m, 62H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.84, 74.13, 59.10, 57.14, 56.62, 56.57, 49.29, 47.69, 46.19, 44.06, 42.47, 42.37, 41.13, 37.58, 36.99,
35.91, 34.92, 34.66, 34.33, 33.53, 31.06, 30.98, 29.98, 28.84, 28.65, 28.33,35.91, 34.92, 34.66, 34.33, 33.53, 31.06, 30.98, 29.98, 28.84, 28.65, 28.33,
27.92, 27.65, 25.06, 24.14, 22.86, 22.80, 17.87, 13.39 27.92, 27.65, 25.06, 24.14, 22.86, 22.80, 17.87, 13.39
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94-3.89 (m, 2H), 2.75-2.40 (m, 14H), 2.24-0.85 (m, 45H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.98, 74.08, 69.06, 59.99, 57.30, 56.64, 56.60, 50.72, 48.22, 47.67, 42.43, 41.05, 37.09, 37.03, 36.43, 36.00, 34.43, 34.37, 33.56, 30.61, 30.52, 28.89, 27.61, 24.36, 23.46, 22.81, 22.74, 17.89, 13.15 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94-3.89 (m, 2H), 2.75-2.40 (m, 14H), 2.24-0.85 (m, 45H), 0.71 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.98, 74.08, 69.06, 59.99, 57.30, 56.64, 56.60, 50.72, 48.22, 47.67, 42.43, 41.05, 37.09, 37.03, 36.43, 36.00, 34.43, 34.37 , 33.56, 30.61, 30.52, 28.89, 27.61, 24.36, 23.46, 22.81, 22.74, 17.89, 13.15
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.70- 0.69 (m, 51H). RMN 13C (62 MHz, CD3OD) : δ (ppm) = 175.80, 69.04, 59.50, 57.50, 57.13, 56.55, 51.69, 46.04, 43.82, 43.69, 42.43, 42.39, 41.21, 41.05, 40.96, 37.60, 37.21, 37.04, 36.80, 36.08, 34.35, 34.19, 33.54, 30.69, 29.45, 28.35, 27.52, 24.78, 23.77, 22.84, 22.77, 21.93, 19.12, 12.39 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.70- 0.69 (m, 51H). 13 C NMR (62 MHz, CD 3 OD): δ (ppm) = 175.80, 69.04, 59.50, 57.50, 57.13, 56.55, 51.69, 46.04, 43.82, 43.69, 42.43, 42.39, 41.21, 41.05, 40.96, 37.60, 37.21 , 37.04, 36.80, 36.08, 34.35, 34.19, 33.54, 30.69, 29.45, 28.35, 27.52, 24.78, 23.77, 22.84, 22.77, 21.93, 19.12, 12.39
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.75- 2.32 (m, 12H), 2.24-0.71 (m, 50H). RMN 13C (62 MHz, CD3OD) : δ (ppm) = 175.84, 72.05, 58.94, 57.64, 57.01, 56.73, 56.57, 46.17, 44.93, 44.82, 44.66, 44.48, 42.41, 41.70, 41.05, 40.80, 36.95, 35.77, 34.41, 34.39, 33.59, 30.54, 30.42, 29.84, 28.09, 27.74, 24.30, 22.83, 22.76, 19.24, 12.82 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.75-2.32 (m, 12H), 2.24-0.71 (m, 50H). 13 C NMR (62 MHz, CD3OD): δ (ppm) = 175.84, 72.05, 58.94, 57.64, 57.01, 56.73, 56.57, 46.17, 44.93, 44.82, 44.66, 44.48, 42.41, 41.70, 41.05, 40.80, 36.95, 35.77. , 34.41, 34.39, 33.59, 30.54, 30.42, 29.84, 28.09, 27.74, 24.30, 22.83, 22.76, 19.24, 12.82
RMN ¾ (250 MHz, CD3OD) : δ (ppm) =3.94 (m, 1H), 2.75-2.37 (m, 10H), 2.24-0.69 (m, 53H). RMN 13C (62 MHz, CD3OD) : δ (ppm) = 175.81, 58.05, 57.59, 56.57, 46.26, 44.06, 43.98, 42.49, 42.41, 41.97, 41.66, 41.14, 37.39, 37.22, 36.97, 36.31, 34.37, 33.51, 31.09, 31.04, 29.43, 27.82, 25.44, 24.36, 22.83, 22.77, 22.11, 19.08, 12.69 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 2.75-2.37 (m, 10H), 2.24-0.69 (m, 53H). 13 C NMR (62 MHz, CD3OD): δ (ppm) = 175.81, 58.05, 57.59, 56.57, 46.26, 44.06, 43.98, 42.49, 42.41, 41.97, 41.66, 41.14, 37.39, 37.22, 36.97, 36.31, 34.37, 33.51 , 31.09, 31.04, 29.43, 27.82, 25.44, 24.36, 22.83, 22.77, 22.11, 19.08, 12.69
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94-3.91 (m, 2H), 2.83-2.53 (m, 13H), 2.26-0.70 (m, 56H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.12, 59.03, 49.98, 49.30, 48.27, 47.76, 45.42, 43.93, 42.41, 40.37, 37.56, 37.01, 35.81, 34.94, 34.41, 33.55, 31.13, 29.98, 28.84, 28.74, 28.51, 27.61, 27.43, 25.03, 23.91, 22.82, 22.76, 17.86, 13.34 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94-3.91 (m, 2H), 2.83-2.53 (m, 13H), 2.26-0.70 (m, 56H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.93, 74.12, 59.03, 49.98, 49.30, 48.27, 47.76, 45.42, 43.93, 42.41, 40.37, 37.56, 37.01, 35.81, 34.94, 34.41, 33.55, 31.13 , 29.98, 28.84, 28.74, 28.51, 27.61, 27.43, 25.03, 23.91, 22.82, 22.76, 17.86, 13.34
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.96-3.94 (m, 2H), 3.79 (m, 1H), 2.85-2.68 (m, 13H), 2.54-0.71 (m, 55H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.91, 74.02, 69.02, 59.34, 50.08, 48.66, 48.21, 47.64, 45.47, 43.52, 43.12, 42.40, 41.16, 40.48, 37.08, 36.87, 36.65, 36.49, 36.35, 35.95, 34.44, 33.56, 31.65, 29.68, 28.87, 28.64, 28.02, 27.84, 27.78, 27.36, 24.36, 23.41, 22.82, 22.76, 17.91, 13.14 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.96-3.94 (m, 2H), 3.79 (m, 1H), 2.85-2.68 (m, 13H), 2.54-0.71 (m, 55H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.91, 74.02, 69.02, 59.34, 50.08, 48.66, 48.21, 47.64, 45.47, 43.52, 43.12, 42.40, 41.16, 40.48, 37.08, 36.87, 36.65, 36.49 , 36.35, 35.95, 34.44, 33.56, 31.65, 29.68, 28.87, 28.64, 28.02, 27.84, 27.78, 27.36, 24.36, 23.41, 22.82, 22.76, 17.91, 13.14
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.89 (m, 1H), 3.74 (m, 1H), 2.70- 2.41 (m, 13H), 2.17-0.64 (m, 56H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.82, 69.03, 59.40, 57.55, 51.70, 50.44, 50.33, 48.27, 45.61, 43.83, 43.63, 42.41, 41.22, 40.95, 40.63, 37.06, 36.76, 36.04, 34.37, 34.21, 33.56, 32.53, 29.46, 29.37, 28.10, 27.98, 24.78, 23.71, 22.83, 22.76, 21.94, 19.11, 12.37 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.89 (m, 1H), 3.74 (m, 1H), 2.70-2.41 (m, 13H), 2.17-0.64 (m, 56H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.82, 69.03, 59.40, 57.55, 51.70, 50.44, 50.33, 48.27, 45.61, 43.83, 43.63, 42.41, 41.22, 40.95, 40.63, 37.06, 36.76, 36.04 , 34.37, 34.21, 33.56, 32.53, 29.46, 29.37, 28.10, 27.98, 24.78, 23.71, 22.83, 22.76, 21.94, 19.11, 12.37
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.75-2.64 (m, 13H), 2.27-0.69 (m, 50H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 176.47, 69.04, 59.40, 57.46, 52.17, 51.69, 50.46, 50.36, 48.27, 45.62, 43.81, 43.63, 41.20, 40.95, 40.63, 37.27, 37.11, 36.90, 36.76, 36.03, 34.19, 32.61, 32.39, 31.97, 29.46, 29.40, 28.11, 28.04, 24.77, 23.72, 21.93, 18.96, 12.37 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.65 (s, 3H), 2.75-2.64 (m, 13H), 2.27-0.69 (m, 50H). 13 C NMR (63 MHz, CD 3 OD): δ (ppm) = 176.47, 69.04, 59.40, 57.46, 52.17, 51.69, 50.46, 50.36, 48.27, 45.62, 43.81, 43.63, 41.20, 40.95, 40.63, 37.27, 37.11 , 36.90, 36.76, 36.03, 34.19, 32.61, 32.39, 31.97, 29.46, 29.40, 28.11, 28.04, 24.77, 23.72, 21.93, 18.96, 12.37
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.73- 2.62 (m, 13H), 2.40-0.70 (m, 55H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.43, 69.05, 59.44, 57.50, 51.67, 50.57, 50.49, 48.89, 48.34, 45.69, 43.83, 43.75, 43.68, 41.62, 41.20, 40.97, 40.70, 37.54, 37.18, 36.79, 36.07, 34.18, 33.23, 33.07, 31.17, 29.89, 29.48, 28.25, 24.79, 23.76, 21.94, 19.23, 14.83, 13.45, 12.40 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.73- 2.62 (m, 13H), 2.40-0.70 (m, 55H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.43, 69.05, 59.44, 57.50, 51.67, 50.57, 50.49, 48.89, 48.34, 45.69, 43.83, 43.75, 43.68, 41.62, 41.20, 40.97, 40.70, 37.54 , 37.18, 36.79, 36.07, 34.18, 33.23, 33.07, 31.17, 29.89, 29.48, 28.25, 24.79, 23.76, 21.94, 19.23, 14.83, 13.45, 12.40
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.98- 2.52 (m, 15H), 2.33-0.71 (m, 54H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.86, 72.04, 58.87, 57.65, 56.76, 55.13, 50.29, 45.73, 45.66, 44.94, 44.66, 44.44, 42.42, 41.69, 40.80, 40.56, 38.81, 36.97, 36.65, 35.74, 34.42, 33.60, 32.03, 29.83, 29.56, 28.02, 24.32, 22.82, 22.76, 22.54, 19.23, 12.80 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.98- 2.52 (m, 15H), 2.33-0.71 (m, 54H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.86, 72.04, 58.87, 57.65, 56.76, 55.13, 50.29, 45.73, 45.66, 44.94, 44.66, 44.44, 42.42, 41.69, 40.80, 40.56, 38.81, 36.97 , 36.65, 35.74, 34.42, 33.60, 32.03, 29.83, 29.56, 28.02, 24.32, 22.82, 22.76, 22.54, 19.23, 12.80
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.98-2.69 (m, 13H), 2.20-0.69 (m, 57H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.85, 59.05, 57.98, 57.65, 49.71, 49.65, 47.94, 45.00, 44.05, 43.58, 42.43, 41.88, 41.59, 39.91, 37.28, 36.98, 36.29, 36.03, 34.38, 33.53, 29.43, 28.88, 27.39, 27.33, 25.38, 24.51, 24.00, 22.81, 22.74, 22.06, 19.04, 12.63 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 2.98-2.69 (m, 13H), 2.20-0.69 (m, 57H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.85, 59.05, 57.98, 57.65, 49.71, 49.65, 47.94, 45.00, 44.05, 43.58, 42.43, 41.88, 41.59, 39.91, 37.28, 36.98, 36.29, 36.03 , 34.38, 33.53, 29.43, 28.88, 27.39, 27.33, 25.38, 24.51, 24.00, 22.81, 22.74, 22.06, 19.04, 12.63
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.05 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.79-2.63 (m, 8H), 2.52-0.95 (m, 54H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.27, 69.02, 59.41, 57.49, 51.69, 50.64, 48.95, 48.27, 47.11, 45.69, 43.84, 43.59, 41.19, 40.95, 40.65, 37.25, 37.10, 37.04, 36.74, 36.00, 34.21, 33.54, 33.38, 32.80, 29.54, 29.37, 27.89, 24.78, 23.70, 21.93, 21.30, 21.12, 19.23, 12.39. NMR ¾ (250 MHz, CD3OD): δ (ppm) = 4.05 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.79-2.63 (m, 8H), 2.52-0.95 (m, 54H), 0.71 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.27, 69.02, 59.41, 57.49, 51.69, 50.64, 48.95, 48.27, 47.11, 45.69, 43.84, 43.59, 41.19, 40.95, 40.65, 37.25, 37.10, 37.04 , 36.74, 36.00, 34.21, 33.54, 33.38, 32.80, 29.54, 29.37, 27.89, 24.78, 23.70, 21.93, 21.30, 21.12, 19.23, 12.39.
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.87- 2.61 (m, 9H), 2.47-0.95 (m, 52H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.86, 69.08, 59.44, 57.54, 51.70, 49.75, 48.34, 45.71, 43.84, 43.66, 41.21, 40.95, 40.70, 37.41, 37.14, 37.06, 36.79, 36.05, 34.37, 34.21, 34.02, 33.94, 33.61, 33.11, 29.80, 29.47, 28.15, 26.81, 26.35, 24.78, 23.73, 21.93, 19.11, 12.37 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.87- 2.61 (m, 9H), 2.47-0.95 (m, 52H), 0.69 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.86, 69.08, 59.44, 57.54, 51.70, 49.75, 48.34, 45.71, 43.84, 43.66, 41.21, 40.95, 40.70, 37.41, 37.14, 37.06, 36.79, 36.05 , 34.37, 34.21, 34.02, 33.94, 33.61, 33.11, 29.80, 29.47, 28.15, 26.81, 26.35, 24.78, 23.73, 21.93, 19.11, 12.37
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.83- 2.60 (m, 13H), 2.46-0.95 (m, 50H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.42, 69.06, 59.47, 57.48, 51.66, 48.99, 48.93, 45.76, 43.83, 43.74, 41.62, 41.20, 40.97, 40.76, 37.74, 37.19, 36.82, 36.10, 34.18, 33.48, 33.23, 31.14, 30.25, 29.89, 29.49, 28.43, 24.80, 23.79, 21.94, 19.23, 14.83, 13.46, 12.40 NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.83-2.60 (m, 13H), 2.46-0.95 (m, 50H), 0.70 ( s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.42, 69.06, 59.47, 57.48, 51.66, 48.99, 48.93, 45.76, 43.83, 43.74, 41.62, 41.20, 40.97, 40.76, 37.74, 37.19, 36.82, 36.10 , 34.18, 33.48, 33.23, 31.14, 30.25, 29.89, 29.49, 28.43, 24.80, 23.79, 21.94, 19.23, 14.83, 13.46, 12.40
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.06 (m, 1H), 3.79 (m, 1H), 3.53 (m, 1H), 2.88-2.61 (m, 12H), 2.49-0.95 (m, 57H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.31, 69.06, 59.45, 57.51, 51.71, 50.68, 48.95, 48.43, 47.13, 45.71, 43.85, 43.67, 41.21, 40.97, 40.72, 37.39, 37.28, 37.13, 36.79, 36.04, 34.21, 33.56, 33.40, 33.16, 31.12, 30.12, 29.78, 29.57, 28.13, 24.79, 23.71, 21.93, 21.28, 21.10, 19.21, 12.36 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 4.06 (m, 1H), 3.79 (m, 1H), 3.53 (m, 1H), 2.88-2.61 (m, 12H), 2.49-0.95 (m, 57H), 0.70 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.31, 69.06, 59.45, 57.51, 51.71, 50.68, 48.95, 48.43, 47.13, 45.71, 43.85, 43.67, 41.21, 40.97, 40.72, 37.39, 37.28, 37.13 , 36.79, 36.04, 34.21, 33.56, 33.40, 33.16, 31.12, 30.12, 29.78, 29.57, 28.13, 24.79, 23.71, 21.93, 21.28, 21.10, 19.21, 12.36
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.97-3.91 (m, 2H), 2.78-2.49 (m, 13H), 2.25-0.95 (m, 51H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.13, 59.15, 53.41, 52.83, 49.35, 48.25, 47.75, 46.14, 43.96, 42.41, 41.01, 37.55, 37.01, 35.85, 34.95, 34.38, 34.14, 33.53, 30.11, 30.05, 29.98, 28.84, 28.55, 27.91, 27.61, 27.24, 25.02, 24.02, 22.82, 22.76, 17.85, 13.35.NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.97-3.91 (m, 2H), 2.78-2.49 (m, 13H), 2.25-0.95 (m, 51H), 0.71 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.93, 74.13, 59.15, 53.41, 52.83, 49.35, 48.25, 47.75, 46.14, 43.96, 42.41, 41.01, 37.55, 37.01, 35.85, 34.95, 34.38, 34.14 , 33.53, 30.11, 30.05, 29.98, 28.84, 28.55, 27.91, 27.61, 27.24, 25.02, 24.02, 22.82, 22.76, 17.85, 13.35.
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.97-3.91 (m, 2H), 3.79 (m, 1H), 2.83-2.39 (m, 15H), 2.27-0.94 (m, 48H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.93, 74.05, 69.04, 59.40, 53.67, 52.87, 52.77, 48.19, 47.64, 46.02, 43.61, 43.15, 42.41, 41.18, 41.01, 37.08, 36.41, 36.00, 34.41, 33.57, 30.20, 29.71, 28.89, 28.05, 27.83, 26.91, 24.36, 23.46, 22.82, 22.76, 17.90, 13.15. 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.97-3.91 (m, 2H), 3.79 (m, 1H), 2.83-2.39 (m, 15H), 2.27-0.94 (m, 48H), 0.71 ( s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.93, 74.05, 69.04, 59.40, 53.67, 52.87, 52.77, 48.19, 47.64, 46.02, 43.61, 43.15, 42.41, 41.18, 41.01, 37.08, 36.41, 36.00 , 34.41, 33.57, 30.20, 29.71, 28.89, 28.05, 27.83, 26.91, 24.36, 23.46, 22.82, 22.76, 17.90, 13.15.
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.80 (m, 1H), 3.41-3.35 (m, 4H), 2.80-2.53 (m, 13H), 2.43-0.96 (m, 50H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.41, 68.97, 59.41, 57.50, 53.29, 52.77, 51.69, 45.66, 43.82, 43.75, 43.46, 41.62, 41.18, 40.91, 40.74, 37.17, 36.68, 35.93, 34.19, 33.23, 31.19, 29.46, 29.21, 27.40, 26.48, 24.77, 23.66, 21.93, 19.24, 14.84, 13.47, 12.41. RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.83- 2.57 (m, 13H), 2.27-0.93 (m, 45H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.89, 69.06, 59.41, 57.64, 57.53, 57.49, 56.98, 54.03, 51.77, 44.82, 43.85, 43.53, 42.43, 41.24, 41.20, 40.95, 39.99, 37.05, 36.71, 35.95, 34.41, 34.27, 33.56, 29.45, 27.67, 24.74, 23.60, 22.80, 22.73, 21.90, 19.07, 12.34.1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.80 (m, 1H), 3.41-3.35 (m, 4H), 2.80-2.53 (m, 13H), 2.43-0.96 (m, 50H), 0.70 ( s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.41, 68.97, 59.41, 57.50, 53.29, 52.77, 51.69, 45.66, 43.82, 43.75, 43.46, 41.62, 41.18, 40.91, 40.74, 37.17, 36.68, 35.93 , 34.19, 33.23, 31.19, 29.46, 29.21, 27.40, 26.48, 24.77, 23.66, 21.93, 19.24, 14.84, 13.47, 12.41. NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.83-2.57 (m, 13H), 2.27-0.93 (m, 45H), 0.69 ( s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.89, 69.06, 59.41, 57.64, 57.53, 57.49, 56.98, 54.03, 51.77, 44.82, 43.85, 43.53, 42.43, 41.24, 41.20, 40.95, 39.99, 37.05 , 36.71, 35.95, 34.41, 34.27, 33.56, 29.45, 27.67, 24.74, 23.60, 22.80, 22.73, 21.90, 19.07, 12.34.
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.83- 2.37 (m, 15H), 2.24-0.95 (m, 49H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.77, 69.01, 59.56, 57.47, 53.55, 52.83, 51.68, 46.23, 43.81, 43.68, 42.38, 41.13, 40.94, 37.67, 37.22, 37.03, 36.81, 36.11, 34.33, 34.19, 33.54, 30.61, 29.46, 28.40, 27.38, 24.78, 23.80, 22.86, 22.79, 21.94, 19.13. NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.83-2.37 (m, 15H), 2.24-0.95 (m, 49H), 0.69 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.77, 69.01, 59.56, 57.47, 53.55, 52.83, 51.68, 46.23, 43.81, 43.68, 42.38, 41.13, 40.94, 37.67, 37.22, 37.03, 36.81, 36.11 , 34.33, 34.19, 33.54, 30.61, 29.46, 28.40, 27.38, 24.78, 23.80, 22.86, 22.79, 21.94, 19.13.
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.80- 2.47 (m, 13H), 2.21-0.95 (m, 57H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 69.09, 59.57, 57.54, 53.56, 52.85, 51.71 , 49.76, 46.22, 43.84, 43.71, 41.13, 40.97, 37.19, 37.05, 36.82, 36.07, 34.37, 34.22, 34.02, 33.94, 33.60, 30.60, 29.47, 28.36, 27.34, 26.81, 26.34, 24.77, 23.73, 21.94, 19.10, 12.36 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.80-2.47 (m, 13H), 2.21-0.95 (m, 57H), 0.69 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.88, 69.09, 59.57, 57.54, 53.56, 52.85, 51.71, 49.76, 46.22, 43.84, 43.71, 41.13, 40.97, 37.19, 37.05, 36.82, 36.07, 34.37 , 34.22, 34.02, 33.94, 33.60, 30.60, 29.47, 28.36, 27.34, 26.81, 26.34, 24.77, 23.73, 21.94, 19.10, 12.36
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.89- 2.52 (m, 13H), 2.37-0.96 (m, 50H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.88, 72.05, 59.99, 57.67, 56.71, 53.38, 52.84, 46.23, 44.94, 44.66, 44.42, 42.43, 40.96, 40.82, 38.80, 36.98, 35.75, 34.40, 33.60, 29.84, 28.10, 24.25, 22.81, 22.75, 19.21, 12.79 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.47 (m, 1H), 2.89- 2.52 (m, 13H), 2.37-0.96 (m, 50H), 0.71 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.88, 72.05, 59.99, 57.67, 56.71, 53.38, 52.84, 46.23, 44.94, 44.66, 44.42, 42.43, 40.96, 40.82, 38.80, 36.98, 35.75, 34.40 , 33.60, 29.84, 28.10, 24.25, 22.81, 22.75, 19.21, 12.79
RMN ^ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 2.97-2.50 (m, 12H), 2.25-0.86 (m, 53H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.87, 59.16, 58.08, 57.63, 53.52, 53.31, 52.85, 46.12, 44.07, 43.92, 43.84, 42.43, 41.99, 41.66, 40.89, 37.36, 37.20, 36.98, 36.33, 36.23, 34.37, 33.90, 33.52, 29.62, 29.43, 27.79, 27.10, 25.41, 24.22, 22.81, 22.75, 22.10, 19.05, 12.66 1 H NMR (250 MHz, CD 3 OD): δ (ppm) = 3.94 (m, 1H), 2.97-2.50 (m, 12H), 2.25-0.86 (m, 53H), 0.69 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.87, 59.16, 58.08, 57.63, 53.52, 53.31, 52.85, 46.12, 44.07, 43.92, 43.84, 42.43, 41.99, 41.66, 40.89, 37.36, 37.20, 36.98 , 36.33, 36.23, 34.37, 33.90, 33.52, 29.62, 29.43, 27.79, 27.10, 25.41, 24.22, 22.81, 22.75, 22.10, 19.05, 12.66
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.05 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.80-2.61 (m, 13H), 2.45-0.95 (m, 58H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.28, 69.07, 59.45, 57.47, 51.67, 50.62, 50.52, 48.89, 48.35, 47.11, 45.71, 43.84, 43.68, 41.19, 40.96, 40.72, 37.56, 37.25, 36.85, 36.79, 36.09, 35.83, 34.19, 33.54, 33.38, 33.21, 29.96, 29.54, 28.30, 24.79, 23.75, 21.93, 21.30, 21.12, 19.23, 12.39 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 4.05 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.80-2.61 (m, 13H), 2.45-0.95 (m, 58H), 0.70 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.28, 69.07, 59.45, 57.47, 51.67, 50.62, 50.52, 48.89, 48.35, 47.11, 45.71, 43.84, 43.68, 41.19, 40.96, 40.72, 37.56, 37.25 , 36.85, 36.79, 36.09, 35.83, 34.19, 33.54, 33.38, 33.21, 29.96, 29.54, 28.30, 24.79, 23.75, 21.93, 21.30, 21.12, 19.23, 12.39
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.76- 2.62 (m, 13H), 2.49-0.95 (m, 57H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.83, 69.04, 59.43, 57.56, 51.70, 50.55, 50.44, 49.74, 48.32, 45.69, 43.83, 43.63, 41.21, 40.95, 40.69, 37.30, 37.05, 36.76, 36.05, 34.39, 34.21, 34.00, 33.92, 33.60, 32.93, 29.56, 29.46, 28.26, 28.06, 26.80, 26.34, 24.77, 23.71, 21.92, 19.12, 12.38. NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 3.79 (m, 1H), 3.61 (m, 1H), 2.76- 2.62 (m, 13H), 2.49-0.95 (m, 57H), 0.69 ( s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.83, 69.04, 59.43, 57.56, 51.70, 50.55, 50.44, 49.74, 48.32, 45.69, 43.83, 43.63, 41.21, 40.95, 40.69, 37.30, 37.05, 36.76 , 36.05, 34.39, 34.21, 34.00, 33.92, 33.60, 32.93, 29.56, 29.46, 28.26, 28.06, 26.80, 26.34, 24.77, 23.71, 21.92, 19.12, 12.38.
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.82- 2.60 (m, 9H), 2.42-0.96 (m, 50H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.90, 69.00, 59.37, 57.63, 51.76, 50.06, 48.65, 45.53, 43.84, 43.45, 42.44, 41.84, 41.73, 41.23, 40.91, 40.60, 37.09, 36.67, 36.35, 34.42, 34.24, 33.57, 30.03, 29.46, 28.25, 27.70, 27.21, 24.74, 23.55, 22.80, 22.73, 21.89, 19.07, 12.33 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.80 (m, 1H), 2.82- 2.60 (m, 9H), 2.42-0.96 (m, 50H), 0.69 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.90, 69.00, 59.37, 57.63, 51.76, 50.06, 48.65, 45.53, 43.84, 43.45, 42.44, 41.84, 41.73, 41.23, 40.91, 40.60, 37.09, 36.67 , 36.35, 34.42, 34.24, 33.57, 30.03, 29.46, 28.25, 27.70, 27.21, 24.74, 23.55, 22.80, 22.73, 21.89, 19.07, 12.33
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.71- 2.60 (m, 13H), 2.46-0.95 (m, 48H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.50, 69.12, 59.49, 57.50, 51.67, 49.87, 45.69, 43.84, 43.76, 41.64, 41.21, 40.97, 40.73, 37.79, 37.25, 37.20, 36.83, 36.08, 34.19, 33.66, 33.24, 31.16, 30.49, 29.49, 28.48, 24.79, 23.76, 21.93, 19.20, 14.80, 13.42, 12.36.NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.79 (m, 1H), 3.38 (m, 4H), 2.71- 2.60 (m, 13H), 2.46-0.95 (m, 48H), 0.70 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.50, 69.12, 59.49, 57.50, 51.67, 49.87, 45.69, 43.84, 43.76, 41.64, 41.21, 40.97, 40.73, 37.79, 37.25, 37.20, 36.83, 36.08 , 34.19, 33.66, 33.24, 31.16, 30.49, 29.49, 28.48, 24.79, 23.76, 21.93, 19.20, 14.80, 13.42, 12.36.
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.05 (m, 1H), 3.79 (m, 1H), 3.53 (m, 1H), 2.82-2.61 (m, 13H), 2.47-0.95 (m, 54H), 0.70 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.15, 69.00, 59.49, 57.41, 51.63, 50.63, 50.60, 50.17, 48.44, 47.07, 45.72, 43.82, 43.73, 41.18, 40.97, 40.73, 37.79, 37.25, 36.82, 36.12, 34.16, 33.62, 33.50, 33.35, 30.52, 29.57, 28.50, 24.82, 23.86, 21.96, 21.34, 21.17, 19.28, 12.46. NMR ¾ (250 MHz, CD3OD): δ (ppm) = 4.05 (m, 1H), 3.79 (m, 1H), 3.53 (m, 1H), 2.82-2.61 (m, 13H), 2.47-0.95 (m, 54H), 0.70 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.15, 69.00, 59.49, 57.41, 51.63, 50.63, 50.60, 50.17, 48.44, 47.07, 45.72, 43.82, 43.73, 41.18, 40.97, 40.73, 37.79, 37.25 , 36.82, 36.12, 34.16, 33.62, 33.50, 33.35, 30.52, 29.57, 28.50, 24.82, 23.86, 21.96, 21.34, 21.17, 19.28, 12.46.
RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.81- 2.48 (m, 9H), 2.40-0.86 (m, 50H), 0.69 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.79, 69.06, 59.48, 59.45, 57.50, 51.68, 50.69, 50.66, 49.01, 48.40, 47.42, 45.77, 43.83, 43.76, 42.56, 42.39, 41.22, 40.97, 40.79, 37.87, 37.30, 37.06, 36.84, 36.12, 34.35, 34.19, 33.59, 33.56, 31.74, 30.46, 29.46, 28.57, 28.47, 27.97, 24.79, 23.82, 22.86, 22.78, 21.95, 19.13, 12.40. RMN ¾ (250 MHz, CD3OD) : δ (ppm) = 4.06 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.80-2.47 (m, 13H), 2.39-0.95 (m, 56H), 0.71 (s, 3H). RMN 13C (63 MHz, CD3OD) : δ (ppm) = 175.29, 69.07, 59.58, 57.47, 53.58, 52.86, 51.70, 50.68, 47.12, 46.26, 43.84, 43.71, 41.16, 40.98, 40.75, 37.26, 36.08, 34.21, 33.53, 33.38, 30.69, 29.56, 28.43, 27.42, 24.79, 23.76, 21.92, 21.29, 21.11, 19.22, 12.38 NMR ¾ (250 MHz, CD3OD): δ (ppm) = 3.94 (m, 1H), 3.79 (m, 1H), 2.81-2.48 (m, 9H), 2.40-0.86 (m, 50H), 0.69 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.79, 69.06, 59.48, 59.45, 57.50, 51.68, 50.69, 50.66, 49.01, 48.40, 47.42, 45.77, 43.83, 43.76, 42.56, 42.39, 41.22, 40.97 , 40.79, 37.87, 37.30, 37.06, 36.84, 36.12, 34.35, 34.19, 33.59, 33.56, 31.74, 30.46, 29.46, 28.57, 28.47, 27.97, 24.79, 23.82, 22.86, 22.78, 21.95, 19.13, 12.40. NMR ¾ (250 MHz, CD 3 OD): δ (ppm) = 4.06 (m, 1H), 3.80 (m, 1H), 3.53 (m, 1H), 2.80-2.47 (m, 13H), 2.39-0.95 ( m, 56H), 0.71 (s, 3H). 13 C NMR (63 MHz, CD3OD): δ (ppm) = 175.29, 69.07, 59.58, 57.47, 53.58, 52.86, 51.70, 50.68, 47.12, 46.26, 43.84, 43.71, 41.16, 40.98, 40.75, 37.26, 36.08, 34.21 , 33.53, 33.38, 30.69, 29.56, 28.43, 27.42, 24.79, 23.76, 21.92, 21.29, 21.11, 19.22, 12.38
Parmi lesdits composés de formule (I), les composés (1), (2), (5), (13), (15), (33) et (34) ou un de leurs sels pharmaceutiquement acceptables, notamment leurs chlorhydrates, sont particulièrement intéressants. Among said compounds of formula (I), the compounds (1), (2), (5), (13), (15), (33) and (34) or a pharmaceutically acceptable salt, in particular their hydrochlorides, are particularly interesting.
Les exemples suivants illustrent en détail la préparation des composés selon l'invention. Les structures des produits obtenus ont été confirmées au moins par les spectres de RMN.  The following examples illustrate in detail the preparation of the compounds according to the invention. The structures of the products obtained were confirmed at least by the NMR spectra.
EXEMPLES EXAMPLES
Toutes les synthèses ont été réalisées avec des solvants purifiés selon les méthodes usuelles. Les réactifs commerciaux sont directement utilisés sans purification préalable.  All the syntheses were carried out with solvents purified according to the usual methods. Commercial reagents are directly used without prior purification.
« Rdt » signifie rendement.  "Yard" means yield.
Exemple 1 : préparation des composés de formule (III) tels que définis ci- dessus Example 1 Preparation of the compounds of formula (III) as defined above
Exemple 1.1 N-isopropyl-désoxycholamide 1  Example 1.1 N-Isopropyl Deoxycholamide 1
Figure imgf000038_0001
Dans un ballon bicol muni d'un barreau aimanté, on place 2 g (5.1 mmol) d' acide déoxycholique dissous dans 20 mL de THF. On additionne en suivant 1.7 équivalents de HOBT (1.36 g, 8.8 mmol) et 1 équivalent de DCC (1.04 g, 5.1mmol). On additionne également 600 d'isopropy lamine (13 mmol) et on place sous agitation 24h à température ambiante. Après évaporation du THF et reprise dans 40 mL de CH2C12 on filtre le précipité qui est lavé avec de l'acétate d'éthyle. Le filtrat est concentré sous vide et purifié par chromatographie sur gel de silice (éluant : acétate d'éthyle/méthanol (9/1)). Le produit désiré 1 est obtenu sous la forme d'un solide blanc (1.9 g).
Figure imgf000038_0001
In a two-necked flask equipped with a magnetic bar, 2 g (5.1 mmol) of deoxycholic acid dissolved in 20 ml of THF are placed. It is added by following 1.7 equivalents of HOBT (1.36 g, 8.8 mmol) and 1 equivalent of DCC (1.04 g, 5.1 mmol). 600 isopropylamine (13 mmol) are also added and the mixture is stirred for 24 hours at room temperature. After evaporation of the THF and recovery in 40 mL of CH 2 Cl 2, the precipitate is filtered and washed with ethyl acetate. The filtrate is concentrated under vacuum and purified by chromatography on silica gel (eluent: ethyl acetate / methanol (9/1)). The desired product 1 is obtained in the form of a white solid (1.9 g).
RMN JH (250 MHz, CDC13) : δ (ppm) = 4.17 (m, 2H), 2.39-0.63 (m, 45H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.39 ; 73.17 ; 71.59 ; 50.36 ; 48.93 ; 48.06 ; 46.76 ; 42.09 ; 41.23 ; 36.26 ; 35.96 ; 35.35 ; 34.14 ; 33.68 ; 33.68 ; 33.51 ; 33.44 ; 31.68 ; 30.65 ; 28.47 ; 27.60 ; 27.17 ; 26.19 ; 25.62 ; 24.95 ; 23.75 ; 23.10 ; 22.68 ; 17.31 ; 12.69. Rdt : 79%. C27H47NO3 H NMR J (250 MHz, CDC1 3): δ (ppm) = 4.17 (m, 2H), 2.39-0.63 (m, 45H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 173.39; 73.17; 71.59; 50.36; 48.93; 48.06; 46.76; 42.09; 41.23; 36.26; 35.96; 35.35; 34.14; 33.68; 33.68; 33.51; 33.44; 31.68; 30.65; 28.47; 27.60; 27.17; 26.19; 25.62; 24.95; 23.75; 23.10; 22.68; 17.31; 12.69. Yield: 79%. C27H47NO3
Les composés 2-7 ont été préparés selon le mode opératoire en considérant l'acide biliaire adéquat de départ. Compounds 2-7 were prepared according to the procedure considering the appropriate starting bile acid.
Exemple 1.2 N-isopropy -chénodésoxycholamide 2 Example 1.2 N-isopropyl-chenodeoxycholamide 2
Figure imgf000039_0001
Figure imgf000039_0001
RMN JH (250 MHz, CDCI3) : δ (ppm) = 3.96 (m, 2H), 3.69 (m, 1H), 3.31 (m, 1H), 2.30-0.75 (m, 41H), 0.50 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 172.88, 72.02, 68.53, 60.46, 55.80, 50.45, 42.69, 41.49, 41.28, 39.83, 39.64, 39.41, 35.47, 35.33, 35.06, 34.60, 33.75, 32.83, 31.82, 30.64, 28.23, 23.71, 22.83, 20.59, 18.42, 14.22, 11.78. Rdt : 67%. C27H47NO3 H NMR J (250 MHz, CDCl3): δ (ppm) = 3.96 (m, 2H), 3.69 (m, 1H), 3.31 (m, 1H), 2.30-0.75 (m, 41H), 0.50 (s, 3H ). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 172.88, 72.02, 68.53, 60.46, 55.80, 50.45, 42.69, 41.49, 41.28, 39.83, 39.64, 39.41, 35.47, 35.33, 35.06, 34.60, 33.75, 32.83 , 31.82, 30.64, 28.23, 23.71, 22.83, 20.59, 18.42, 14.22, 11.78. Yield: 67%. C27H47NO3
Exemple 1.3 N-méthyl-chénodésoxycholamide 3 Example 1.3 N-methyl-chenodeoxycholamide 3
0  0
Figure imgf000039_0002
RMN *H (250 MHz, CDC13) : δ (ppm) = 3.78 (m, 1H), 3.60 (s, 3H), 3.39 (m, 1H), 2.35-2.06 (m, 3H), 1.98-0.73 (m, 31H), 0.59 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 189.68, 174.82, 71.99, 66.51, 55.78, 51.54, 50.46, 42.69, 41.49, 39.86, 39.64, 39.41, 35.39, 35.08, 34.62, 32.84, 31.02, 30.67, 28.17, 23.71, 22.80, 20.59, 18.28, 11.78. Rdt : 57%. C25H42NO3 -isopropyl-lithocholamide 4
Figure imgf000039_0002
1 H NMR (250 MHz, CDCl 3 ): δ (ppm) = 3.78 (m, 1H), 3.60 (s, 3H), 3.39 (m, 1H), 2.35-2.06 (m, 3H), 1.98-0.73 ( m, 31H), 0.59 (s, 3H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 189.68, 174.82, 71.99, 66.51, 55.78, 51.54, 50.46, 42.69, 41.49, 39.86, 39.64, 39.41, 35.39, 35.08, 34.62, 32.84, 31.02, 30.67 , 28.17, 23.71, 22.80, 20.59, 18.28, 11.78. Yield: 57%. C25H42NO3 -isopropyl-lithocholamide 4
Figure imgf000040_0001
Figure imgf000040_0001
RMN ^ (250 MHz, CDCb) : δ (ppm) = 4.1 1-3.40 (m, 3H), 2.1 1-0.55 (m, 44H). RMN 13C (63 MHz, CDCb) : δ (ppm) = 171.71 , 71.87, 58.53, 56.01 , 42.76, 42.09, 41.21 , 40.43, 40.20, 36.45, 35.88, 35.50, 35.38, 34.58, 34.00, 33.84, 31.81 , 30.55, 28.29, 27.20, 26.43, 24.98, 24.22, 23.40, 22.88, 20.84, 18.43, 12.05. Rdt : 92%. C27H47NO2 1 H NMR (250 MHz, CDCl 3): δ (ppm) = 4.1 1-3.40 (m, 3H), 2.1 1-0.55 (m, 44H). RMN 1 3 C (63 MHz, CDCl): δ (ppm) = 171.71, 71.87, 58.53, 56.01, 42.76, 42.09, 41.21, 40.43, 40.20, 36.45, 35.88, 35.50, 35.38, 34.58, 34.00, 33.84, 31.81, 30.55, 28.29, 27.20, 26.43, 24.98, 24.22, 23.40, 22.88, 20.84, 18.43, 12.05. Yield: 92%. C27H47NO2
Exemple 1.5 N-isopro Example 1.5 N-isopro
Figure imgf000040_0002
Figure imgf000040_0002
RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.19-385 (m, 3H), 3.42 (m, 1H), 2.22-0.87 (m, 40H), 0.66 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.88, 73.24, 71.86, 68.50, 60.46, 49.07, 46.27, 41.50, 41.33, 39.33, 35.35, 34.78, 34.86, 33.81, 33.06, 31.78, 30.18, 28.01, 27.57, 26.22, 24.91, 23.26, 22.63, 22.39, 21.09, 17.41, 14.20, 12.40 Rdt : 83%. C27H47NO4 Exemple 1.6 N-isopropyl-ursodésoxycholamide 6 H NMR J (250 MHz, CDCl3): δ (ppm) = 4.19-385 (m, 3H), 3.42 (m, 1H), 2.22-0.87 (m, 40H), 0.66 (s, 3H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 173.88, 73.24, 71.86, 68.50, 60.46, 49.07, 46.27, 41.50, 41.33, 39.33, 35.35, 34.78, 34.86, 33.81, 33.06, 31.78, 30.18, 28.01 , 27.57, 26.22, 24.91, 23.26, 22.63, 22.39, 21.09, 17.41, 14.20, 12.40 Yield: 83%. C27H47NO4 Example 1.6 N-Isopropyl ursodeoxycholamide 6
Figure imgf000041_0001
Figure imgf000041_0001
RMN ^ (250 MHz, CDC13) : δ (ppm) = 4.01-3.92 (m, 1H), 3.59-3.33 (m, 2H), 2.20-0.79 (m, 41H), 0.52 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.72, 71.38, 71.35, 55.69, 54.78, 43.68, 43.51, 42.14, 41.51, 40.09, 39.24, 37.14, 36.91, 35.42, 34.93, 34.01, 33.69, 31.97, 30.15, 28.66, 26.87, 25.51, 24.84, 23.38, 22.67, 21.16, 18.45, 12.07. Rdt : 70%. C27H47NO3 1 H NMR (250 MHz, CDCl 3 ): δ (ppm) = 4.01-3.92 (m, 1H), 3.59-3.33 (m, 2H), 2.20-0.79 (m, 41H), 0.52 (s, 3H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 173.72, 71.38, 71.35, 55.69, 54.78, 43.68, 43.51, 42.14, 41.51, 40.09, 39.24, 37.14, 36.91, 35.42, 34.93, 34.01, 33.69, 31.97 , 30.15, 28.66, 26.87, 25.51, 24.84, 23.38, 22.67, 21.16, 18.45, 12.07. Yield: 70%. C27H47NO3
Exemple 1.7 N,N-diéthyl-chénodésoxycholamide 7 Example 1.7 N, N-diethyl-chenodeoxycholamide 7
Figure imgf000041_0002
Figure imgf000041_0002
RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.03 (m, 1H), 3.76-3.57 (m, 2H), 3.37-3.22 (m, 5H), 2.31- 0.83 (m, 38H), 0.59 (s, 3H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 173.38, 72.36, 68.85, 67.57, 60.94, 56.44, 50.94, 43.16, 42.55, 42.07, 40.58, 40.21, 39.93, 36.13, 35.92, 35.56, 35.20, 33.33,32.08, 31.13, 30.47, 28.75, 24.19, 23.35, 21.57, 21.13, 19.07, 14.96, 14.71, 13.61, 12.30.
Figure imgf000041_0003
H NMR J (250 MHz, CDCl3): δ (ppm) = 4.03 (m, 1H), 3.76-3.57 (m, 2H), 3.37-3.22 (m, 5H), 2.31- 0.83 (m, 38H), 0.59 (s, 3H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 173.38, 72.36, 68.85, 67.57, 60.94, 56.44, 50.94, 43.16, 42.55, 42.07, 40.58, 40.21, 39.93, 36.13, 35.92, 35.56, 35.20, 33.33. , 32.08, 31.13, 30.47, 28.75, 24.19, 23.35, 21.57, 21.13, 19.07, 14.96, 14.71, 13.61, 12.30.
Figure imgf000041_0003
Exemple 2 : préparation des composés de formule (II) téls que définis ci- dessus Example 2 Preparation of Compounds of Formula (II) as Defined Above
Exemple 2.1 3-oxo-N-isopropyl-désoxycholamide 8 Example 2.1 3-Oxo-N-isopropyl-deoxycholamide 8
Figure imgf000041_0004
Dans un ballon bicol muni d'un barreau aimanté et surmonté d'un Dean-Stark, on place 2 g (5 mmol) de N-isopropyl-désoxycholamide 1 dissous dans 40 mL de toluène et 30 mL d'acétone. On additionne en suivant 2.2 équivalents de tri-feri-butylate d'aluminium (2.7 g, 11 mmol). Le mélange est porté à reflux du toluène pendant 8h. Après refroidissement, le mélange est lavé à trois reprises avec 30 mL d'acide sulfurique 2N puis avec 30 mL d'eau. Après séchage sur sulfate de sodium anhydre et fîltration, le filtrat est évaporé sous vide. Le produit brut ainsi obtenu est purifié par chromatographie sur gel de silice (éluant : acétate d'éthyle). Le produit désiré 8 est obtenu sous la forme d'un solide blanc. RMN JH (250 MHz, CD CL) : δ (ppm) = 4.09-4.01 (m, 2H), 2.78-0.68 (m, 43H). RMN 13C (63 MHz, CDC13) : δ (ppm) = 213.51, 172.55, 72.85, 48.06, 47.24, 46.52, 44.23, 42.28, 41.16, 37.08, 36.82, 35.63, 35.12, 34.34, 33.74, 33.69, 31.61, 28.87, 27.44, 26.48, 25.41, 23.52, 22.78, 22.75, 22.32, 17.42, 12.72. Rdt : 49%. C27H45NO3
Figure imgf000041_0004
In a two-caliber flask equipped with a magnetized bar and surmounted by a Dean-Stark, 2 g (5 mmol) of N-isopropyl-deoxycholamide 1 dissolved in 40 ml of toluene and 30 ml of acetone are placed. 2.2 equivalents of aluminum tri-tert-butylate (2.7 g, 11 mmol) are added. The mixture is refluxed toluene for 8h. After cooling, the mixture is washed three times with 30 mL of 2N sulfuric acid and then with 30 mL of water. After drying over anhydrous sodium sulphate and filtration, the filtrate is evaporated under vacuum. The crude product thus obtained is purified by chromatography on silica gel (eluent: ethyl acetate). The desired product 8 is obtained in the form of a white solid. H NMR J (250 MHz, CD CL): δ (ppm) = 4.09-4.01 (m, 2H), 2.78-0.68 (m, 43H). 13 C NMR (63 MHz, CDCl 3 ): δ (ppm) = 213.51, 172.55, 72.85, 48.06, 47.24, 46.52, 44.23, 42.28, 41.16, 37.08, 36.82, 35.63, 35.12, 34.34, 33.74, 33.69, 31.61, 28.87, 27.44, 26.48, 25.41, 23.52, 22.78, 22.75, 22.32, 17.42, 12.72. Yield: 49%. C27H45NO3
Les composés 9-12 ont tous été produits selon le même mode opératoire que celui développé pour la synthèse du composé 8 décrit ci-dessus en considérant le diol de départ adéquat (composés 2,5-7) préalablement préparé. Compounds 9-12 were all produced according to the same procedure as that developed for the synthesis of compound 8 described above by considering the appropriate starting diol (compounds 2.5-7) previously prepared.
Figure imgf000042_0001
Figure imgf000042_0001
RMN JH (250 MHz, CDCL) : δ (ppm) = 4.07 (m, 1H), 3.91 (m, 1H), 2.44-0.64 (m, 43H). RMN 13C (63 MHz, CDCL) : δ (ppm) = 213.40, 172.57, 68.28, 55.79, 50.25, 45.59, 43.19, 42.65, 41.15, 39.46, 39.29, 36.93, 36.77, 35.41, 35.25, 33.82, 33.69, 33.16, 31.69, 23.60, 22.79, 22.76, 21.88, 20.91, 18.34, 11.73. Rdt : 58%. C27H45NO3 Exemple 2.3 3-oxo-N-isop H NMR J (250 MHz, CDCl): δ (ppm) = 4.07 (m, 1H), 3.91 (m, 1H), 2.44-0.64 (m, 43H). 13 C NMR (63 MHz, CDCL): δ (ppm) = 213.40, 172.57, 68.28, 55.79, 50.25, 45.59, 43.19, 42.65, 41.15, 39.46, 39.29, 36.93, 36.77, 35.41, 35.25, 33.82, 33.69, 33.16, 31.69, 23.60, 22.79, 22.76, 21.88, 20.91, 18.34, 11.73. Yield: 58%. C27H45NO3 Example 2.3 3-oxo-N-isop
Figure imgf000043_0001
Figure imgf000043_0001
RMN *H (250 MHz, CDC13) : δ (ppm) = 3.99-3.86 (m, 3H), 2.41-0.62 (m, 42H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.74, 173.30, 72.97, 68.97, 46.55, 46.39, 45.37, 43.01, 41.55, 41.08, 39.11, 36.68, 36.54, 35.35, 34.82, 33.93, 32.99, 31.41, 28.29, 27.51, 26.70, 23.14, 22.54, 21.38, 17.20, 12.34. Rdt : 58%. C27H45NO4 1 H NMR (250 MHz, CDCl 3 ): δ (ppm) = 3.99-3.86 (m, 3H), 2.41-0.62 (m, 42H). 13 C NMR (63 MHz, CDCl 3): δ (ppm) = 213.74, 173.30, 72.97, 68.97, 46.55, 46.39, 45.37, 43.01, 41.55, 41.08, 39.11, 36.68, 36.54, 35.35, 34.82, 33.93, 32.99, 31.41 , 28.29, 27.51, 26.70, 23.14, 22.54, 21.38, 17.20, 12.34. Yield: 58%. C27H45NO4
Exemple 2.43-oxo-N-isop Example 2.43-oxo-N-isop
Figure imgf000043_0002
Figure imgf000043_0002
RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.07 (m, 1H), 3.58 (m, 1H), 2.56-0.67 (m, 43H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 212.12, 172.65, 70.58, 55.61, 54.87, 44.31, 43.64, 43.20, 43.04, 41.13, 39.90, 39.27, 36.93, 36.28, 36.15, 35.27, 34.30, 33.67, 31.71, 28.53, 26.72, 22.69, 22.66, 22.57, 21.54, 18.40, 12.04. Rdt : 67%. C27H45NO3 H NMR J (250 MHz, CDCl3): δ (ppm) = 4.07 (m, 1H), 3.58 (m, 1H), 2.56-0.67 (m, 43H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 212.12, 172.65, 70.58, 55.61, 54.87, 44.31, 43.64, 43.20, 43.04, 41.13, 39.90, 39.27, 36.93, 36.28, 36.15, 35.27, 34.30, 33.67. , 31.71, 28.53, 26.72, 22.69, 22.66, 22.57, 21.54, 18.40, 12.04. Yield: 67%. C27H45NO3
Exemple 2.5 3-oxo-N,N-diéthyl-chénodésoxycholamide 12 Example 2.5 3-oxo-N, N-diethyl-chenodeoxycholamide 12
Figure imgf000043_0003
Figure imgf000043_0003
RMN JH (250 MHz, CDCI3) : δ (ppm) = 3.89 (m, 1H), 3.29 (m, 4H), 2.43-0.67 (m, 42H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.48, 172.63, 68.08, 55.85, 50.21, 45.59, 43.25, 42.57, 41.90, 39.97, 39.43, 39.29, 36.90, 36.77, 35.52, 35.22, 33.83, 33.10, 31.42, 29.82, 28.14, 23.57, 21.86, 20.90, 18.43, 14.34, 13.01, 11.71. Rdt : 65%. C28H47NO3 Les composés 13 et 14 ont été produits à partir du N-méthyl-chénodésoxycholamide 3 et du N-isopropyl-lithocholamide 4 respectivement selon le même mode opératoire que celui utilisé pour la synthèse du composé 8 décrit ci-dessus, à l'exception des conditions de purification par chromatographie sur gel de silice des produits bruts qui ont été modifiées (éluant : acétate d'éthyle/éther de pétrole (1/1)). H NMR J (250 MHz, CDCl3): δ (ppm) = 3.89 (m, 1H), 3.29 (m, 4H), 2.43-0.67 (m, 42H). 13 C NMR (63 MHz, CDCl 3): δ (ppm) = 213.48, 172.63, 68.08, 55.85, 50.21, 45.59, 43.25, 42.57, 41.90, 39.97, 39.43, 39.29, 36.90, 36.77, 35.52, 35.22, 33.83, 33.10 , 31.42, 29.82, 28.14, 23.57, 21.86, 20.90, 18.43, 14.34, 13.01, 11.71. Yield: 65%. C28H47NO3 Compounds 13 and 14 were produced from N-methyl-chenodeoxycholamide 3 and N-isopropyl-lithocholamide 4 respectively according to the same procedure as that used for the synthesis of compound 8 described above, with the exception of purification conditions by chromatography on silica gel of the crude products which have been modified (eluent: ethyl acetate / petroleum ether (1/1)).
Exemple 2.6 3-oxo-N-méthyl-chénodésoxycholamide 13 Example 2.6 3-oxo-N-methyl-chenodeoxycholamide 13
Figure imgf000044_0001
Figure imgf000044_0001
RMN JH (250 MHz, CDC13) : δ (ppm) = 3.79 (m, 1H), 3.54 (s, 3H), 2.34-0.58 (m, 37H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.33, 174.42, 67.69, 55.44, 51.18, 49.90, 45.30, 42.99, 42.28, 39.17, 39.02, 36.60, 36.52, 35.00, 34.96, 33.63, 32.83, 30.61, 27.84, 23.26, 21.61, 20.65, 17.95, 11.45. Rdt : 42%. C25H41NO3 H NMR J (250 MHz, CDC1 3): δ (ppm) = 3.79 (m, 1H), 3.54 (s, 3H), 2.34-0.58 (m, 37H). 13 C NMR (63 MHz, CDCl 3): δ (ppm) = 213.33, 174.42, 67.69, 55.44, 51.18, 49.90, 45.30, 42.99, 42.28, 39.17, 39.02, 36.60, 36.52, 35.00, 34.96, 33.63, 32.83, 30.61 , 27.84, 23.26, 21.61, 20.65, 17.95, 11.45. Yield: 42%. C25H41NO3
Exemple 2.7 3-oxo-N-isopro l-lithocholamide 14 Example 2.7 3-Oxo-N-isopropyl-lithocholamide 14
Figure imgf000044_0002
Figure imgf000044_0002
RMN JH (250 MHz, CDCI3) : δ (ppm) = 4.06 (m, 1H), 2.67-0.65 (m, 44H). RMN 13C (63 MHz, CDCI3) : δ (ppm) = 213.44, 172.55, 56.32, 55.93, 44.23, 42.66, 42.26, 41.06, 40.58, 39.94, 37.12, 36.90, 35.38, 34.77, 33.70, 31.69, 28.11, 26.50, 25.65, 24.05, 22.74, 22.71, 22.55, 21.08, 18.30, 11.96. Rdt : 37%. C27H45NO2 H NMR J (250 MHz, CDCl3): δ (ppm) = 4.06 (m, 1H), 2.67-0.65 (m, 44H). 13 C NMR (63 MHz, CDCl3): δ (ppm) = 213.44, 172.55, 56.32, 55.93, 44.23, 42.66, 42.26, 41.06, 40.58, 39.94, 37.12, 36.90, 35.38, 34.77, 33.70, 31.69, 28.11, 26.50 , 25.65, 24.05, 22.74, 22.71, 22.55, 21.08, 18.30, 11.96. Yield: 37%. C27H45NO2
Exemple 3 : préparation des composés de formule (I) Example 3 Preparation of Compounds of Formula (I)
Les composés selon l'invention ont tous été préparés par amination réductrice des précurseurs cétoniques préparés précédemment à l'exemple 2 (composés 8-14) en présence de la chaîne polyamine appropriée. Exemple 3.1 préparation du composé (1) The compounds according to the invention were all prepared by reductive amination of the ketone precursors prepared above in Example 2 (compounds 8-14) in the presence of the appropriate polyamine chain. Example 3.1 Preparation of the compound (1)
Dans un ballon tricol muni d'une agitation magnétique, 100 mg de 3-oxo-N- isopropyl-désoxycholamide 8 (0.23 mmol) sont dissous dans 7 mL de méthanol. On additionne en suivant 3 équivalents de tétraisopropylate de titane (205 μί, 0.7 mmol) puis 2 équivalents de norspermine (95 μί, 0.46 mmol). Après agitation pendant 12h à température ambiante, on place le ballon dans un bain de glace et on ajoute sous agitation 4 équivalents de borohydrure de sodium (35 mg, 0.92 mmol). Après agitation pendant 2h et retour à température ambiante, on additionne 300 d'eau pour terminer la réaction. Après lh d'agitation supplémentaire, le mélange est filtré sur Célite, rincé à l'ammoniaque puis au méthanol et évaporé sous vide. Le produit brut ainsi obtenu est purifié par chromatographie sur gel de silice (éluant : dichlorométhane/méthanol/ammoniaque (7/3/1)). Le composé (1) est obtenu sous la forme d'une huile jaune. Rdt : 40%.  In a three-necked flask equipped with magnetic stirring, 100 mg of 3-oxo-N-isopropyl-deoxycholamide 8 (0.23 mmol) are dissolved in 7 ml of methanol. It is added by following 3 equivalents of titanium tetraisopropylate (205 μί, 0.7 mmol) then 2 equivalents of norspermine (95 μί, 0.46 mmol). After stirring for 12 h at room temperature, the flask is placed in an ice bath and 4 equivalents of sodium borohydride (35 mg, 0.92 mmol) are added with stirring. After stirring for 2 hours and returning to ambient temperature, 300 parts of water are added to complete the reaction. After stirring for a further hour, the mixture is filtered through Celite, rinsed with ammonia then with methanol and evaporated under vacuum. The crude product thus obtained is purified by chromatography on silica gel (eluent: dichloromethane / methanol / aqueous ammonia (7/3/1)). The compound (1) is obtained in the form of a yellow oil. Yield: 40%.
Exemple 3.2 préparation des composés (2), (25), (3), (20) et (30) Example 3.2 Preparation of Compounds (2), (25), (3), (20) and (30)
Les composés (2), (25), (3), (20) et (30) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3-oxo-N-isopropyl-désoxycholamide 8 et en considérant la chaîne polyamine adéquate.  The compounds (2), (25), (3), (20) and (30) were prepared according to the same procedure developed for the synthesis of the compound (1) using 3-oxo-N as starting precursor. isopropyl-deoxycholamide 8 and considering the appropriate polyamine chain.
Le composé (2) est obtenu avec un rendement de 36%. (C33H62N4O2). Les composés The compound (2) is obtained in a yield of 36%. (C33H62N4O2). Compounds
(25), (3), (20) et (30) sont obtenus avec des rendements respectifs de 70% (C34H64N4O2), 58% (C37H69N5O2), 43% (C37H73N7O2) et 38% (C37H71N5O2). (25), (3), (20) and (30) are obtained with respective yields of 70% (C34H64N4O2), 58% (C37H69N5O2), 43% (C37H73N7O2) and 38% (C37H71N5O2).
Exemple 3.3 préparation des composés (31), (4), (5), (26), (6) et (21) Example 3.3 Preparation of compounds (31), (4), (5), (26), (6) and (21)
Les composés (31), (4), (5), (26), (6) et (21) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3-oxo-N-isopropyl-cholamide 10 et en considérant la chaîne polyamine adéquate. The compounds (31), (4), (5), (26), (6) and (21) were prepared according to the same procedure developed for the synthesis of the compound (1) using as starting precursor the 3 -oxo-N-isopropyl-cholamid and considering the appropriate polyamine chain.
Le composé (31) est obtenu avec un rendement de 37% (C37H71N5O3). Les composés (31), (4), (5), (26), (6) et (21) sont obtenus avec des rendements respectifs de 38% (C36H69N5O3), 47 % (C33H62N4O3), 24% (C34H64N4O3), 40% (C37H69N5O3) et 32%. C37H73N7O3. Exemple 3.4 préparation des composés (32), (7), (8), (27), (9) et (22) The compound (31) is obtained with a yield of 37% (C 37 H 71 N 5 O 3). The compounds (31), (4), (5), (26), (6) and (21) are obtained with respective yields of 38% (C36H69N5O3), 47% (C33H62N4O3), 24% (C34H64N4O3), 40% (C37H69N5O3) and 32%. C37H73N7O3. Example 3.4 Preparation of Compounds (32), (7), (8), (27), (9) and (22)
Les composés (32), (7), (8), (27), (9) et (22) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3-oxo-N-isopropyl-chénodésoxycholamide 9 et en considérant la chaîne polyamine adéquate. The compounds (32), (7), (8), (27), (9) and (22) were prepared according to the same procedure developed for the synthesis of the compound (1) using as starting precursor the 3 -oxo-N-isopropyl-chenodeoxycholamide 9 and considering the appropriate polyamine chain.
Le composé (32) est obtenu avec un rendement de 51% (C37H71N5O2). Les composés (7), (8), (27), (9) et (22) sont obtenus avec des rendements respectifs de 20% (C36H69N5O2), 55% (C33H62N4O2), 65% (C34H64N4O2), 15% (C37H69N5O2) et 26% (C37H73N7O2).  The compound (32) is obtained in a yield of 51% (C 37 H 71 N 5 O 2). The compounds (7), (8), (27), (9) and (22) are obtained with respective yields of 20% (C36H69N5O2), 55% (C33H62N4O2), 65% (C34H64N4O2), 15% (C37H69N5O2). ) and 26% (C37H73N7O2).
Exemple 3.5 préparation des composés (33), (10), (11) et (12) Les composés (33), (10), (11) et (12) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3-oxo-N-méthyl-chénodésoxycholamide 13 et en considérant la chaîne polyamine adéquate. Example 3.5 Preparation of the compounds (33), (10), (11) and (12) The compounds (33), (10), (11) and (12) were prepared according to the same procedure developed for the synthesis of compound (1) using as starting precursor 3-oxo-N-methyl-chenodeoxycholamide 13 and considering the appropriate polyamine chain.
Le composé (33) est obtenu avec un rendement de 36% (C35H67N5O2). Les composés (10), (11) et (12) sont obtenus avec des rendements respectifs de 58% (C34H65N5O2), 51% (C31H58N4O2) et 48% (C35H65N5O2).  The compound (33) is obtained with a yield of 36% (C35H67N5O2). The compounds (10), (11) and (12) are obtained with respective yields of 58% (C34H65N5O2), 51% (C31H58N4O2) and 48% (C35H65N5O2).
Exemple 3.6 préparation des composés (34) et (13) Example 3.6 Preparation of compounds (34) and (13)
Les composés (34) et (13) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3- oxo-N,N-diéthyl-chénodésoxycholamide 12 et en considérant la chaîne polyamine adéquate. Compounds (34) and (13) were prepared according to the same procedure developed for the synthesis of compound (1) using as starting precursor 3-oxo-N, N-diethyl-chenodeoxycholamide 12 and considering the chain adequate polyamine.
Le composé (34) est obtenu avec un rendement de 44% (C38H73N5O2) et le composé (13) avec un rendement de 58% (C34H64N4O). Exemple 3.7 préparation des composés (35), (14), (15), (28), (16) et (23) The compound (34) is obtained with a yield of 44% (C38H73N5O2) and the compound (13) with a yield of 58% (C34H64N4O). Example 3.7 Preparation of Compounds (35), (14), (15), (28), (16) and (23)
Les composés (35), (14), (15), (28), (16) et (23) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3-oxo-N-isopropyl-ursodésoxycholamide 11 et en considérant la chaîne polyamine adéquate. The compounds (35), (14), (15), (28), (16) and (23) were prepared according to the same procedure developed for the synthesis of the compound (1) using as starting precursor the 3 -oxo-N-isopropyl ursodeoxycholamide 11 and considering the appropriate polyamine chain.
Le composé (35) est obtenu avec un rendement de 36% (C37H71N5O2). Les composés (14), (15), (28), (16) et (23) sont obtenus avec des rendements respectifs de 44% (C36H69N5O2), 34%, (C33H62N4O2), 30% (C34H64N4O2), 53% (C37H69N5O2) et 38% (C37H73N7O2).  The compound (35) is obtained with a yield of 36% (C 37 H 71 N 5 O 2). The compounds (14), (15), (28), (16) and (23) are obtained with yields of 44% (C36H69N5O2), 34%, (C33H62N4O2), 30% (C34H64N4O2), 53% ( C37H69N5O2) and 38% (C37H73N7O2).
Exemple 3.8 préparation des composés (36), (17), (18), (29), (19) et (24) Les composés (36), (17), (18), (29), (19) et (24) ont été préparés selon le même mode opératoire développé pour la synthèse du composé (1) en utilisant comme précurseur de départ le 3-oxo-N-isopropyl-lithocholamide 14 et en considérant la chaîne polyamine adéquate. Example 3.8 Preparation of compounds (36), (17), (18), (29), (19) and (24) Compounds (36), (17), (18), (29), (19) and (24) were prepared according to the same procedure developed for the synthesis of compound (1) using as starting precursor 3-oxo-N-isopropyl-lithocholamide 14 and considering the proper polyamine chain.
Le composé (36) est obtenu avec un rendement de 28% (C37H71N5O). Les composés (17), (18), (29), (19) et (24) sont obtenus avec des rendements respectifs de 22% The compound (36) is obtained in a yield of 28% (C 37 H 71 N 5 O). The compounds (17), (18), (29), (19) and (24) are obtained with respective yields of 22%
(C36H69N5O), 32% (C33H62N4O), 39% (C34H64N4O), 18% (C37H69N5O) et 45% (C37H73N7O). (C36H69N5O), 32% (C33H62N4O), 39% (C34H64N4O), 18% (C37H69N5O) and 45% (C37H73N7O).
Exemple 4 : Activités antibactériennes intrinsèques des composés de formule (I) 1) Préparation de la préculture Example 4 Intrinsic antibacterial activities of the compounds of formula (I) 1) Preparation of the preculture
Deux tubes ont été préparés :  Two tubes were prepared:
Un témoin négatif (2 mL de milieu de culture stérile)  A negative control (2 mL of sterile culture medium)
Un témoin positif (1940 de milieu de culture + 40μΙ, de DMSO + 20 de la suspension bactérienne) à partir d'une souche biologique décongelée (La conservation des souches biologiques est réalisée à - 80°C dans du glycérol).  A positive control (1940 culture medium + 40 μΙ, DMSO + 20 of the bacterial suspension) from a thawed biological strain (The conservation of biological strains is carried out at -80 ° C. in glycerol).
Les tubes ont été incubés à 37° C pendant 24 heures à 100 tours/minute.  The tubes were incubated at 37 ° C for 24 hours at 100 rpm.
Les germes ont été manipulés sous une hotte dans le laboratoire de type L2 et avant toute manipulation un cycle d'UV a été programmé et seul du matériel stérile a été utilisé. Un test de toxicité des solvants (méthanol, éthanol, DMSO) a été réalisé et ces derniers se sont montrés non toxiques à des concentrations inférieures ou égales à 2%. Les composés chimiques à tester ont été préparées dans un mélange de DMSO/méthanol (50/50) à une concentration de 5 mg/mL. The germs were handled under a hood in the laboratory type L2 and before any manipulation a UV cycle was programmed and only sterile material was used. A solvent toxicity test (methanol, ethanol, DMSO) was carried out and these were non-toxic at concentrations of less than or equal to 2%. The chemical compounds to be tested were prepared in a mixture of DMSO / methanol (50/50) at a concentration of 5 mg / ml.
2) Préparation de la microplaque pour la détermination de la concentration minimale d'inhibition (CMI) 2) Preparation of the microplate for the determination of the minimum concentration of inhibition (MIC)
Après 24 heures d'incubation, une mesure de la densité optique a été effectuée à l'aide d'un spectrophotomètre à 600 nm en prélevant ΙΟΟμί de la suspension bactérienne diluée dans 900 μΐ, du milieu de culture stérile. Ce test a nécessité l'utilisation d'une plaque de 96 puits et le volume nécessaire de la suspension microbienne à ensemencer a été calculé pour une DO correspondante à une valeur égale à 0.01 dans chaque puits. Dans cette plaque, la première ligne correspondait au témoin négatif (195 μΐ, de milieu de culture stérile dans chaque puit), la deuxième ligne au témoin positif (milieu de culture ensemencé et additionné de 2 % de DMSO), la troisième ligne a été chargée deux fois en suspension bactérienne, 8 μΐ, de produit à tester ont été placés dans chaque puit. Par la suite, une dilution en cascade au demi a été réalisée à partir de cette ligne.  After 24 hours of incubation, a measurement of the optical density was carried out using a spectrophotometer at 600 nm by taking ΙΟΟμί of the bacterial suspension diluted in 900 μΐ, sterile culture medium. This test required the use of a 96-well plate and the necessary volume of the microbial suspension to be seeded was calculated for an OD corresponding to a value equal to 0.01 in each well. In this plate, the first line corresponded to the negative control (195 μl of sterile culture medium in each well), the second line to the positive control (culture medium inoculated and supplemented with 2% DMSO), the third line was loaded twice in bacterial suspension, 8 μΐ of product to be tested were placed in each well. Subsequently, a half-cascade dilution was made from this line.
La première colonne a servi comme témoin d'inhibition. Un filtre stérile a ensuite été placé sur la microplaque permettant le passage des gaz mais pas des contaminants. La microplaque a été incubée à 37° C dans une atmosphère humide durant 24h.  The first column served as an inhibition control. A sterile filter was then placed on the microplate allowing the passage of gases but not contaminants. The microplate was incubated at 37 ° C in a humid atmosphere for 24 hours.
NB : Le milieu utilisé est le milieu Mueller-Hinton (MH) pour les bactéries. Tous les tests ont été réalisés en duplicate. 3) Cytotoxicité  NB: The medium used is the Mueller-Hinton (MH) medium for bacteria. All tests were done in duplicate. 3) Cytotoxicity
Le test WST1 a été utilisé pour mesurer l'activité cytotoxique des produits. C'est un test colorimétrique qui permet de mesurer la viabilité et le taux de prolifération cellulaire. Il est basé sur le clivage de sels de tétrazolium incolores WST-1 (4-[3-(4- iodophényl)-2-(4-nitrophényl)-2H-5-tétrazolio]-l,3-benzène disulfonate) par les déshydrogénases mitochondriales en dérivé formazan de couleur jaune, quantifiables par spectrophotométrie à 420-480 nm. Le test WST1 a été effectué sur des cellules d'ovaires de hamster chinois. Les cellules CHO-Kl (ATCC, USA) sont maintenues en culture dans du milieu Mac Coy's 5A additionné de 10% de sérum de veau fœtal, de 2 mM de L-glutamine et d'un mélange de pénicilline streptomycine (100 U/ml : 10 μg/ml). On incube à 37°C sous atmosphère enrichie en C02 (5%) et repiquées tous les deux jours. The WST1 test was used to measure the cytotoxic activity of the products. It is a colorimetric test that measures the viability and rate of cell proliferation. It is based on the cleavage of colorless tetrazolium salts WST-1 (4- [3- (4-iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazole] -1,3-benzene disulfonate) by the mitochondrial dehydrogenases in yellow formazan derivative, quantifiable by spectrophotometry at 420-480 nm. The WST1 test was performed on Chinese hamster ovary cells. The CHO-K1 cells (ATCC, USA) are maintained in culture in Mac Coy's 5A medium supplemented with 10% fetal calf serum, 2 mM L-glutamine and a penicillin streptomycin mixture (100 U / ml). 10 μg / ml). Incubated at 37 ° C under a CO 2 -rich atmosphere (5%) and subcultured every other day.
Les cellules sont transférées dans des plaques de 96 puits (25000 cellules/mL) dans du milieu de Me Coy's 5A complet, et maintenues pendant 24 h à 37°C sous atmosphère humide enrichie en CO2 (5%). Des concentrations croissantes de produits à tester sont ajoutées dans les puits en doubles essais et 8 témoins de croissance contenant les cellules dans le milieu seul sont inclus dans chaque série de tests. Après 24 heures à 37°C (5% de CO2), le milieu de culture est éliminé, les cellules sont rincées dans du tampon phosphate (PB S) et 50 de  The cells are transferred to 96-well plates (25,000 cells / ml) in complete Me Coy's 5A medium and maintained for 24 h at 37 ° C in a CO2 enriched wet atmosphere (5%). Increasing concentrations of test products are added to the wells in double runs and 8 growth controls containing the cells in the medium alone are included in each test run. After 24 hours at 37 ° C. (5% CO 2), the culture medium is removed, the cells are rinsed in phosphate buffer (PB S) and 50
PBS contenant 10% de réactif WST1, sont additionnés dans chaque puits. Après 20 minutes d'incubation à 37°C, la lecture des résultats s'effectue par spectrophotométrie à 450 nm.  PBS containing 10% WST1 reagent are added to each well. After incubation for 20 minutes at 37 ° C., the results are read spectrophotometrically at 450 nm.
Les résultats sont exprimés sous forme de relations dose-réponse, modélisés par une analyse de régression non-linéaire à l'aide du logiciel TableCurve. La Concentration Inhibitrice 50% (CI50) représente la concentration en produit capable de réduire de 50% la viabilité cellulaire.  The results are expressed as dose-response relationships, modeled by non-linear regression analysis using the TableCurve software. 50% Inhibitory Concentration (IC50) represents the concentration of product capable of reducing cell viability by 50%.
4) Lecture des résultats 4) Reading the results
Après incubation, le filtre a été remplacé par un film transparent, ensuite une lecture de DO a été réalisée dans un spectrophotomètre à plaques IEMS à 620 nm. Un calcul de la concentration minimale d'inhibition (CMI) a été réalisé.  After incubation, the filter was replaced with a transparent film, then an OD reading was performed in an IEMS plate spectrophotometer at 620 nm. A calculation of the minimum concentration of inhibition (MIC) was performed.
Les résultats sont rassemblés dans le tableau III qui suit. Tableau III : Activités antibactériennes intrinsèques des composés de formule (I) The results are summarized in Table III which follows. Table III: Intrinsic antibacterial activities of the compounds of formula (I)
Figure imgf000050_0001
(35) 16 16 8 64 64 64 32 64 55
Figure imgf000050_0001
(35) 16 16 8 64 64 64 32 64 55
(14) 16 32 4 128 128 128 64 128 90(14) 16 32 4 128 128 128 64 128 90
(15) 28 56 7 112 56 112 56 112 140(15) 28 56 7 112 56 112 56 112 140
(28) 28 28 14 56 56 112 112 112 28(28) 28 28 14 56 56 112 112 112 28
(16) 60 60 15 120 60 120 >120 >120 -(16) 60 60 15 120 60 120> 120> 120 -
(23) 32 32 16 64 128 128 128 128 115(23) 32 32 16 64 128 128 128 128 115
(36) 3,75 3,75 1,87 7,5 7,5 15 15 30 36(36) 3.75 3.75 1.87 7.5 7.5 15 15 30 36
(17) 8 8 4 8 16 32 64 32 17(17) 8 8 4 8 16 32 64 32 17
(18) 6 3 0,8 12 26 3 104 26 20(18) 6 3 0.8 12 26 3 104 26 20
(29) 14 14 7 28 28 28 112 112 6(29) 14 14 7 28 28 28 112 112 6
(19) 8 4 4 15 30 30 120 30 12(19) 8 4 4 15 30 30 120 30 12
(24) 8 8 4 16 32 64 128 128 35(24) 8 8 4 16 32 64 128 128 35
(42) 4 4 1 30 > 120 30 30 60 40(42) 4 4 1 30> 120 30 30 60 40
(43) 16 16 8 60 125 60 125 60 38(43) 16 16 8 60 125 60 125 60 38
(44) 2 4 2 n.d. 15 30 60 60 75(44) 2 4 2 n. 15 30 60 60 75
(53) 4 4 2 2 60 15 30 15 30(53) 4 4 2 2 60 15 30 15 30
(45) 7 4* 2 14 110 14* 110 28* 60(45) 7 4 * 2 14 110 14 * 110 28 * 60
(46) 8 2 2 30 > 120 30 60 120 50(46) 8 2 2 30> 120 30 60 120 50
(37) 4 2 1 4 15 4 30 15 35(37) 4 2 1 4 15 4 30 15 35
(50) 4 2 2 4 > 130 17 17 17 25(50) 4 2 2 4> 130 17 17 17 25
(54) 4 4 2 2 125 8 32 16 22(54) 4 4 2 2 125 8 32 16 22
(38) 4 4 2 4 30 15 30 30 12(38) 4 4 2 4 30 15 30 30 12
(51) 4 2 1 2 105 16 16 16 13(51) 4 2 1 2 105 16 16 16 13
(55) 2 4 2 n.d. 112 55 14 112 80(55) 2 4 2 n. 112 55 14 112 80
(52) 7 4 2 14 112 28 56 112 80(52) 7 4 2 14 112 28 56 112 80
(39) 2 1 1 n.d. 120 4 15 8 n.d.(39) 2 1 1 n. 120 4 15 8 n.d.
(40) 4 2 2 2 32 8 8 8 n.d.(40) 4 2 2 2 32 8 8 8 n.d.
(56) 4 4 4 2 65 16 130 65 n.d. (47) 4 8 8 8 130 32 130 32 n.d. (56) 4 4 4 2 65 16 130 65 nd (47) 4 8 8 8 130 32 130 32 nd
(48) 30 15 8 60 > 120 120 120 120 42 (48) 30 15 8 60> 120 120 120 120 42
(49) 4 4 2 15 120 30 120 60 6 (49) 4 4 2 15 120 30 120 60 6
Exemple 5 : Activités antibactériennes des composés de formule (I) en association avec de la doxycycline EXAMPLE 5 Antibacterial Activities of the Compounds of Formula (I) in Combination with Doxycycline
Préparation de la microplaque pour la détermination de la concentration minimale d'inhibition (CMI) de l'association d'un composé de formule (I) et de la doxycycline Preparation of the microplate for determination of the minimum concentration of inhibition (MIC) of the combination of a compound of formula (I) and doxycycline
Cette méthode nécessite l'utilisation d'une plaque de 96 puits, 100 μΐ, d'un milieu de culture liquide est déposé dans chaque puits puis ensemencé avec la suspension microbienne précédemment préparée. Le volume nécessaire à ensemencer est calculé pour une DO de 0.01 qui correspond à environ 5.106 bactéries dans chaque puit. Dans cette plaque, la première ligne correspond à un témoin négatif (200 de milieu de culture stérile dans chaque puits), la deuxième ligne à un témoin positif (100 de milieu de culture stérile + 100 μΐ, de la suspension bactérienne), la troisième ligne contient 192 μΐ, de milieu de culture, 8 μΐ, de composé de formule (I) à tester sont placés dans chaque puits. Par la suite, une dilution en cascade est réalisée à partir de cette ligne. On additionne ensuite dans chaque puits des lignes 3 à 8 μί d'une solution de doxycycline (1 mg dissout dans 20 mL) pour obtenir une concentration finale en antibiotique de 2μg/mL. On additionne ensuite 92 μΐ, de suspension bactérienne dans les lignes 3 à 8. La lecture des résultats (la détermination de la CMI (2 μg/mL de doxyccyline) en présence de X μg/mL de composé de formule (I)) se fait après 24 heures d'incubation à 37° dans une atmosphère humide. Après 24 heures d'incubation à 37°C, 40 μΐ, d'iodure de nitro tétrazolium sont rajoutés dans chaque puits permettant de révéler la présence de bactéries vivantes en colorant le milieu en rose. This method requires the use of a 96-well plate, 100 μl, a liquid culture medium is deposited in each well and then inoculated with the previously prepared microbial suspension. The volume necessary to seed is calculated for an OD of 0.01 which corresponds to approximately 5.10 6 bacteria in each well. In this plate, the first line corresponds to a negative control (200 of sterile culture medium in each well), the second line to a positive control (100 of sterile culture medium + 100 μl, of the bacterial suspension), the third line contains 192 μΐ of culture medium, 8 μΐ, of compound of formula (I) to be tested are placed in each well. Subsequently, cascade dilution is performed from this line. 3 to 8 μί of a doxycycline solution (1 mg dissolved in 20 ml) are then added to each well to obtain a final antibiotic concentration of 2 μg / ml. 92 μΐ of bacterial suspension are then added in lines 3 to 8. The results are read (the determination of the MIC (2 μg / mL doxycylin) in the presence of X μg / mL of compound of formula (I)) is after 24 hours incubation at 37 ° in a humid atmosphere. After 24 hours of incubation at 37 ° C., 40 μl of nitro tetrazolium iodide are added to each well, making it possible to reveal the presence of living bacteria by coloring the medium in pink.
Sur la souche Gram-négative de P. aeruginosa (PAOl), la doxycycline possède une CMI de 40 μg/mL.  On the Gram-negative P. aeruginosa (PAO1) strain, doxycycline has a MIC of 40 μg / mL.
Les résultats sont consignés dans le tableau IV. Ils indiquent la concentration en composés de formule (I) nécessaire pour permettre de restaurer l'activité de la doxycycline (2 μg/mL). Tableau IV : Potentialisation de l'activité de la doxycycline à 2μg/mL en présence des composés de formule (I) The results are shown in Table IV. They indicate the concentration of compounds of formula (I) necessary to restore the activity of doxycycline (2 μg / mL). TABLE IV Potentiation of Doxycycline Activity at 2 μg / mL in the Presence of Compounds of Formula (I)
CMI - P. aeruginosa (1051575) vg/mL MIC - P. aeruginosa (1051575) vg / mL
Composé No Teneur en composé de formule (I) pour restaurer l'activité de la Compound No. A compound content of formula (I) for restoring the activity of the
doxycycycline (à 2 g/mL)  doxycycycline (at 2 g / mL)
(Mg/mL)  (Mg / mL)
(1 ) 1  (1) 1
(2) 0,9  (2) 0.9
(25) 2  (25) 2
(3) 2  (3) 2
(20) 4  (20) 4
(30) 1  (30) 1
(31 ) 1  (31) 1
(4) 1  (4) 1
(5) 1  (5) 1
(26) 4  (26) 4
(6) 8  (6) 8
(32) 1  (32) 1
(7) 1  (7) 1
(8) 2  (8) 2
(27) 2  (27) 2
(9) 2  (9) 2
(22) 4  (22) 4
(33) 1  (33) 1
(10) 1  (10) 1
(1 1 ) 2  (1 1) 2
(12) 8  (12) 8
(34) 2  (34) 2
(13) 2  (13) 2
(35) 2  (35) 2
(14) 1  (14) 1
(15) 1 (28) 7 (15) 1 (28) 7
(36) 0,5  (36) 0.5
(17) 2  (17) 2
(18) 0,8  (18) 0.8
(29) 7  (29) 7
(19) 8  (19) 8
(24) 8  (24) 8
(42) 1  (42) 1
(43) 1  (43) 1
(44) 2  (44) 2
(53) 2  (53) 2
(45) 7  (45) 7
(46) 2  (46) 2
(37) 2  (37) 2
(50) 2  (50) 2
(54) 2  (54) 2
(38) 2  (38) 2
(51 ) 2  (51) 2
(55) 2  (55) 2
(52) 3,5  (52) 3.5
(39) 2  (39) 2
(40) 2  (40) 2
(56) 2  (56) 2
(47) 2  (47) 2
(48) 4  (48) 4
(49) 4  (49) 4
L'utilisation de faibles quantités de composés de formule (I) permet de restaurer (de réduire) la concentration nécessaire en antibiotique pour tuer la souche considérée. On constate ainsi une très bonne synergie de certains composés avec la doxycycline restaurant ainsi l'activité de cet antibiotique à de faibles concentrations d'utilisation (2 μg/mL). The use of small amounts of compounds of formula (I) makes it possible to restore (reduce) the concentration necessary for the antibiotic to kill the strain in question. There is thus a very good synergy of certain compounds with doxycycline thus restoring the activity of this antibiotic at low concentrations of use (2 μg / ml).
En particulier, les composés (2), (9), (25) et (36) permettent d'atteindre une synergie remarquable lorsqu'ils sont administrés avec la doxycycline à 2 μg/mL. Exemple 6 : Activité antibactérienne des composés de formule (I) en association avec Pampicilline, l'érythromycine et le chloramphénicol (souche bactérienne : P. aeruginosa 1051575) In particular, compounds (2), (9), (25) and (36) make it possible to achieve remarkable synergy when administered with doxycycline at 2 μg / ml. Example 6: Antibacterial activity of the compounds of formula (I) in combination with ampicillin, erythromycin and chloramphenicol (bacterial strain: P. aeruginosa 1051575)
Le mode opératoire est totalement similaire à celui indiqué dans l'exemple 5 ci-dessus. 8 d'une solution d'antibiotique considéré (1 mg dissous dans 20 mL) sont additionnés pour obtenir une concentration finale en antibiotique de 2μg/mL à la place de 8 d'une solution de doxycycline.  The procedure is completely similar to that shown in Example 5 above. 8 of an antibiotic solution considered (1 mg dissolved in 20 ml) are added to obtain a final antibiotic concentration of 2 μg / ml instead of 8 of a doxycycline solution.
Les résultats sont consignés dans le tableau V. Ils indiquent la concentration en composé de formule (I) nécessaire pour permettre de restaurer l'activité de l'antibiotique considéré. The results are shown in Table V. They indicate the concentration of the compound of formula (I) necessary to restore the activity of the antibiotic in question.
Tableau V : Potentialisation de l 'activité de l'antibiotique considéré à 2μg/mL en présence des composés de formule (I) Table V: Potentiation of the activity of the antibiotic considered at 2 μg / ml in the presence of the compounds of formula (I)
CMI P. aeruginosa (1051575) (pg/mL) MIC P. aeruginosa (1051575) (μg / mL)
composé +  compound +
composé + composé +  compound + compound +
érythromycin  erythromycin
ampicilline2 chloramphénicol4 ampicillin 2 chloramphenicol 4
e3 e 3
4 Mg/imL 2 pg/mL 4 pg/mL 2 pg/mL  4 Mg / mL 2 μg / mL 4 μg / mL 2 μg / mL
(2) 28 3* 0.9 0.9  (2) 28 3 * 0.9 0.9
(25) 56 28 2 n. d. (25) 56 28 2 n. d.
(42) n. d. 8 n. d. 2 (42) n. d. 8 n. d. 2
(5) 64 32* 2 4  (5) 64 32 * 2 4
(21 ) n. d. 30 n. d. 8  (21) n. d. N. d. 8
(43) n. d. 30 n. d. 4  (43) n. d. N. d. 4
(7) 15 15 2 n. d. (7) 15 n 2 d.
(8) 27 27 2 n. d.(8) 27 27 2 n. d.
(27) 64 28 1 4 (27) 64 28 1 4
(44) n. d. 8 n. d. 4  (44) n. d. 8 n. d. 4
(45) n. d. 28 n. d. 7 (37) n . d . 7 n . d . 2(45) nb 28 nd 7 (37) n. d. 7 n. d. 2
(50) n . d . 4 n . d . 2 (50) n. d. 4 n. d. 2
(51 ) n . d . 8 n . d . 2  (51) n. d. 8 n. d. 2
(55) n . d . 7 n . d . 2  (55) n. d. 7 n. d. 2
(35) 64 32 2 n . d . (35) 64 32 2 n. d.
(15) 1 10 55 2 7 (15) 1 10 55 2 7
(49) n . d . 30 n . d . 4  (49) n. d. N. d. 4
2 CMI ampicilline : 200 μg/mL 2 MIC ampicillin: 200 μg / mL
3 CMI érythromycine : 200 μg/mL  3 MIC erythromycin: 200 μg / mL
4 CMI chloramphénicol : 200 μg/mL  4 MIC chloramphenicol: 200 μg / mL
n. d. : non déterminé  not. d. : not determined
On constate ainsi une très bonne synergie de certains composés avec divers antibiotiques classiques, à de faibles concentrations d'utilisation. There is thus a very good synergy of certain compounds with various conventional antibiotics, at low concentrations of use.
Exemple 7 : Activité antifongique des composés de formule (I) 1) Préparation de la préculture Example 7 Antifungal Activity of the Compounds of Formula (I) 1) Preparation of Preculture
Deux tubes ont été préparés :  Two tubes were prepared:
Un témoin négatif (2 mL de milieu de culture stérile Mueller Hinton MH) Un témoin positif (1980 μΐ, de milieu de culture + 20 μΐ, de la suspension de levures ou champignons) à partir d'une souche biologique décongelée (La conservation des souches biologiques est réalisée à - 80°C dans du glycérol).  A negative control (2 ml of sterile Mueller Hinton MH culture medium) A positive control (1980 μl, culture medium + 20 μl, suspension of yeasts or fungi) from a thawed biological strain (Conservation of biological strains is carried out at -80 ° C in glycerol).
Les tubes ont été incubés à 37° C pendant 24 heures à 100 tours/minute.  The tubes were incubated at 37 ° C for 24 hours at 100 rpm.
Les composés chimiques à tester ont été préparés à une concentration de 5 mg/mL (sous forme de chlorhydrate dans l'eau). 2) Préparation de la microplaque pour la détermination de la concentration minimale d'inhibition (CMI)  The chemical compounds to be tested were prepared at a concentration of 5 mg / mL (as hydrochloride in water). 2) Preparation of the microplate for the determination of the minimum concentration of inhibition (MIC)
La CMI est obtenue en utilisant la méthode de micro dilution en cascade dans des plaques stériles de 96 puits. On place tout d'abord 100 de milieu de culture MH dans chaque puit, on rajoute ensuite dans les premiers puits 8 μΐ, de la solution (5mg/mL) de la molécule à tester. On complète en milieu pour obtenir un volume total de 200 μΐ^ dans ces puits. On réalise alors une dilution en série en prélevant 100 μΐ, dans le premier puit puis de façon successive de puit en puit. On rajoute en suivant 100 μΐ, d'inoculat contenant 2-6 105 CFU de levures ou champignons dans chaque puit. Certains puits sont réservés pour des contrôles positifs et négatifs. Après 24 heures d'incubation on mesure la CMI comme étant la plus basse concentration capable d'inhiber la pousse fongique. MIC is obtained using the cascade micro dilution method in sterile 96-well plates. Firstly, 100 μl of culture medium MH are placed in each well, then, in the first 8 μΐ wells, the solution (5 mg / ml) of the test molecule is added. We complete in the middle to obtain a total volume of 200 μΐ ^ in these wells. Serial dilution is then carried out by taking 100 μΐ, in the first well then successively from well to well. We add by following 100 μΐ of inoculum containing 2-6 10 5 CFU of yeasts or fungi in each well. Some wells are reserved for positive and negative controls. After 24 hours of incubation, the MIC is measured as the lowest concentration capable of inhibiting the fungal growth.
3) Lecture des résultats  3) Reading the results
Après incubation, une lecture de Densité Optique (DO) a été réalisée dans un spectrophotomètre à plaques IEMS à 620 nm. Un calcul de la concentration minimale d'inhibition (CMI) a été réalisé.  After incubation, an Optical Density (OD) reading was performed in an IEMS plate spectrophotometer at 620 nm. A calculation of the minimum concentration of inhibition (MIC) was performed.
Figure imgf000057_0001
Figure imgf000057_0001
n. d. : non déterminé  not. d. : not determined
Ces résultats démontrent une activité antifongique intéressante sur 2 souches certain nombre de composés de formule (I). These results demonstrate antifungal activity of interest on 2 strains number of compounds of formula (I).
Ainsi, les composés de l'invention, de formule (I), (F), (la), (Ib) ou (le), et plus particulièrement les composés (1) à (56) ou l'un de leurs sels pharmaceutiquement acceptables démontrent une activité antibactérienne et antifongique. Ces composés sont utiles pour le traitement d'infections bactériennes, notamment des infections bactériennes à Gram positif telles que des infections à Staphylococcus aureus, Staphylococcus intermedius ou Staphylococcus faecalis et/ou à Gram négatif telles que Escherichia Coli et Pseudonomas aeruginosa. Thus, the compounds of the invention of formula (I), (F), (Ia), (Ib) or (Ie), and more particularly the compounds (1) to (56) or a salt thereof pharmaceutically acceptable demonstrate antibacterial and antifungal activity. These compounds are useful for the treatment of bacterial infections, including gram-positive bacterial infections such as Staphylococcus aureus, Staphylococcus intermedius or Staphylococcus faecalis and / or Gram-negative infections such as Escherichia coli and Pseudonomas aeruginosa.
Les composés de formule (I), (Γ), (la), (Ib), (le) ou (Id), et plus particulièrement les composés (1) à (56) ou l'un de leurs sels pharmaceutiquement acceptables selon l'invention sont notamment utiles pour le traitement antibiotique d'infections bactériennes, notamment de souches de bactéries Gram-positives ou Gram- négatives, chez l'homme ou l'animal. A titre d'exemple, les composés selon l'invention sont utiles pour le traitement de mammites, de métrites, d'infection dentaire, d'infection urinaire, d'affection digestive, de pyodermites ou encore d'otites chez l'homme ou l'animal. Les composés selon l'invention, sont également utiles en tant que revêtement empêchant la prolifération bactérienne, pour la fabrication de produits destinés à détruire les bio films ou à empêcher leur formation. Ces composés peuvent être mis en œuvre dans un dispositif médical, par exemple : cathéters, prothèses, implants, appareils de dialyse, instruments chirurgicaux, sutures ou pansements.  The compounds of formula (I), (Γ), (Ia), (Ib), (Ie) or (Id), and more particularly by the compounds (1) to (56) or one of their pharmaceutically acceptable salts according to the invention are particularly useful for the antibiotic treatment of bacterial infections, including strains of Gram-positive or Gram-negative bacteria, in humans or animals. By way of example, the compounds according to the invention are useful for the treatment of mastitis, metritis, dental infection, urinary tract infection, digestive disease, pyoderma or otitis in humans or the animal. The compounds according to the invention are also useful as a coating preventing bacterial proliferation, for the production of products intended to destroy bio-films or to prevent their formation. These compounds can be used in a medical device, for example: catheters, prostheses, implants, dialysis machines, surgical instruments, sutures or dressings.
La mammite ou mastite est rinflammation de la mamelle chez les mammifères, c'est une infection courante en élevage des femelles laitières (vaches, brebis, chèvres, bufflonnes et chamelles). Elle est caractérisée par la présence dans le lait de cellules inflammatoires (leucocytes) et éventuellement de bactéries. Cette inflammation peut avoir des conséquences cliniques avec modification de l'aspect du lait, inflammation visible de la mamelle (tuméfaction, douleur, œdème) et éventuellement atteinte de l'état général. Le plus souvent la maladie demeure subclinique avec altération de la composition du lait et diminution de la production. La mammite résulte d'une infection de la mamelle par des bactéries plus ou moins adaptées à ce biotope. En élevage laitier spécialisé, les mammites provoquent des pertes économiques importantes (lait non produit, impropre à l'usage, altération de la qualité du lait) et constituent un risque de santé publique (bactéries pathogènes et résidus antibiotiques). Les mammites sont dues à la pénétration puis au développement d'une bactérie dans la glande mammaire. L'entrée du germe se fait généralement par l'extrémité du trayon. Une mammite ne concerne donc en général pas tous les quartiers du pis de l'animal. Les principales bactéries responsables de mammite peuvent être regroupées en deux ensembles, en fonction de leur réservoir de contamination. Les germes se trouvant à la surface de la mamelle : Staphylocoques, Streptococcus agalactiae, Streptococcus disgalactiae, Streptococcus uberis. Ces bactéries sont principalement responsables de mammites sub-cliniques (non détectables à l'œil nu) qu'il est parfois difficile de guérir en cours de lactation, la période de tarissement est alors mise à profit pour traiter les quartiers infectés aux antibiotiques. Les germes se trouvant dans l'environnement (litière) : par exemple, Streptococcus uberis, Escherichia coli. Ces bactéries entraînent généralement des mammites cliniques, qui peuvent aller jusqu'à la mort rapide de l'animal en l'absence de traitement adapté. Les mammites à mycoplasmes posent encore des problèmes dans les cheptels caprins, même si elles ont actuellement quasiment disparu des troupeaux bovins. Mastitis or mastitis is mammalian inflammation of the udder, it is a common infection in breeding dairy females (cows, ewes, goats, buffaloes and camels). It is characterized by the presence in milk of inflammatory cells (leucocytes) and possibly bacteria. This inflammation can have clinical consequences with a change in the appearance of the milk, visible inflammation of the udder (swelling, pain, edema) and possibly impairment of the general condition. Most often the disease remains subclinical with alteration of milk composition and decrease of production. Mastitis results from infection of the udder by bacteria more or less adapted to this biotope. In specialized dairy farming, mastitis causes significant economic losses (unprocessed milk, unfit for use, deterioration of milk quality) and constitutes a public health risk (pathogenic bacteria and antibiotic residues). Mastitis is due to the penetration and development of a bacterium in the mammary gland. The entry of the germ is generally done by the end of the teat. Mastitis does not usually affect all quarters of the udder of the animal. The main bacteria responsible for mastitis can be grouped into two sets, depending on their contamination tank. Germs on the surface of the udder: Staphylococci, Streptococcus agalactiae, Streptococcus disgalactiae, Streptococcus uberis. These bacteria are mainly responsible for subclinical mastitis (not detectable to the naked eye) that is sometimes difficult to cure during lactation, the dry period is then used to treat infected quarters with antibiotics. Germs in the environment (litter): for example, Streptococcus uberis, Escherichia coli. These bacteria usually cause clinical mastitis, which can lead to the rapid death of the animal in the absence of appropriate treatment. Mycoplasma mastitis still poses problems in goat herds, even though they have now virtually disappeared from cattle herds.
La métrite est une inflammation de l'ensemble de la paroi utérine. Elle peut affecter différentes espèces de mammifères domestiques (ruminants, chevaux, porcins, chien, chat) et les animaux sauvages et les humains. Elle est causée par une infection bactérienne et elle est presque toujours observée après une mise bas anormale ou une infection utérine importante. Sa gravité s'échelonne d'une infection subclinique à une maladie déclarée avec fièvre et diminution de la production de lait. Dans le cas des vaches, la métrite peut prédisposer à la cétose, au déplacement de la caillette et à d'autres troubles du post-partum. Elle peut également aboutir à une baisse de la fertilité, temporaire ou permanente, et même, dans certains cas, à la mort de l'animal. La métrite est souvent liée à une contamination de l'utérus par la bactérie Arcanobacterium pyogenes, soit seule soit conjointement à d'autres micro -organismes pathogènes tels que : Fusobacterium necrophorum, Bacteroides spp. ou Escherichia coli. Juste après le vêlage, l'utérus constitue un environnement idéal pour la croissance bactérienne. Durant la première semaine post- partum, jusqu'à 90% des vaches sont victimes d'une infection utérine d'origine bactérienne.  Metritis is an inflammation of the entire uterine wall. It can affect different species of domestic mammals (ruminants, horses, pigs, dogs, cats) and wild animals and humans. It is caused by a bacterial infection and is almost always observed after abnormal calving or significant uterine infection. Its severity ranges from a subclinical infection to a declared disease with fever and decreased milk production. In the case of cows, metritis may predispose to ketosis, abomasum displacement, and other postpartum disorders. It can also lead to a decrease in fertility, temporary or permanent, and even, in some cases, to the death of the animal. Metritis is often associated with contamination of the uterus by the bacterium Arcanobacterium pyogenes, either alone or in combination with other pathogenic micro-organisms such as: Fusobacterium necrophorum, Bacteroides spp. or Escherichia coli. Just after calving, the uterus is an ideal environment for bacterial growth. During the first postpartum week, up to 90% of cows are infected with uterine bacterial infections.
La pyodermite est une maladie cutanée purulente, qui peut être aiguë ou chronique, locale ou diffuse. La pyodermite est étymo logiquement une infection de la peau. Elle est d'origine externe, causée par une bactérie, généralement le staphylocoque ou le Streptococcus pyogenes. Une pyodermite peut être circonscrite ou généralisée. Cette maladie est fréquente chez le chien, mais peut affecter toutes les espèces ayant des pathogènes proches, dont l'espèce humaine. Chez le chien, on observe souvent une dermatite pyotraumatique. Il s'agit d'une lésion cutanée résultant d'une compulsion à griffer, mordiller et lécher une partie du corps. Dès que la lésion est assez importante, une infection secondaire par des bactéries opportunistes peut survenir, amenant l'animal à mordiller ou à se griffer davantage. La plupart des animaux souvent affectés ont des allergies : particulièrement les animaux allergiques aux puces. Cependant, n'importe quelle irritation cutanée peut provoquer une dermatite pyotraumatique. Pyoderma is a purulent skin disease, which can be acute or chronic, local or diffuse. Pyoderma is etymologically an infection of the skin. It is of external origin, caused by a bacterium, usually Staphylococcus or Streptococcus pyogenes. A pyoderma can be circumscribed or generalized. This disease is common in dogs, but can affect all species with similar pathogens, including humans. In dogs, pyotraumatic dermatitis is often observed. This is a skin lesion resulting from a compulsion to scratch, chew and lick part of the body. Once the lesion is large enough, a secondary infection by opportunistic bacteria can occur, causing the animal to bite or scratch more. Most of the animals that are often affected have allergies: especially animals allergic to fleas. However, any skin irritation can cause pyotraumatic dermatitis.
La maladie parodontale ou infection dentaire est une maladie pouvant affecter toutes les espèces, dont l'homme. C'est la principale cause de maladie dentaire chez le chien et elle est fréquente chez le chat. Pourtant caractérisée par une mauvaise haleine, elle est souvent non identifiée par le propriétaire. Sa prévention passe par des soins réguliers car elle peut entraîner la perte des dents voire des infections graves. La présence de bactéries dans la bouche est normale mais lorsqu'elles se développent trop rapidement, elles peuvent entraîner la formation de plaque dentaire. Si la plaque s'accumule et n'est pas éliminée, une gingivite (inflammation des gencives) peut apparaître. À ce stade, le traitement peut être complètement curatif. Cependant, en l'absence de traitement, la maladie évolue en périodontite caractérisée par une inflammation plus importante des gencives, des dépôts de tartre sur les dents et la disparition de l'os et des structures de soutien entourant la dent. L'atteinte peut être prise en charge mais est irréversible. La parodontite peut entraîner la perte des dents et la propagation d'infections graves au niveau du foie, du cœur ou des poumons.  Periodontal disease or dental infection is a disease that can affect all species, including humans. It is the leading cause of dental disease in dogs and is common in cats. Yet characterized by bad breath, it is often unidentified by the owner. Its prevention requires regular care because it can lead to loss of teeth or serious infections. The presence of bacteria in the mouth is normal but when they grow too quickly, they can cause plaque formation. If the plaque builds up and is not cleared, gingivitis (inflammation of the gums) may occur. At this point, the treatment can be completely curative. However, in the absence of treatment, the disease progresses into periodontitis characterized by increased inflammation of the gums, scale deposits on the teeth and loss of bone and supporting structures surrounding the tooth. The attack can be managed but is irreversible. Periodontitis can lead to tooth loss and the spread of serious infections in the liver, heart or lungs.
La cystite, ou infection urinaire, est une maladie pouvant affecter toutes les espèces dont l'homme. Cette pathologie est particulièrement fréquente chez le chat mais se rencontre également fréquemment chez le chien. Elle peut être consécutive à des traumatismes locaux tels que des calculs urinaires ou à des infections d'origine exogène.  Cystitis, or urinary tract infection, is a disease that can affect all species including humans. This pathology is particularly common in cats but is also common in dogs. It may be secondary to local trauma such as urinary stones or infections of exogenous origin.
Les affections digestives, et plus particulièrement celles conduisant à des diarrhées sont des affections très fréquentes chez l'homme et l'animal, en particulier chez le chien et le chat. Ces affections sont souvent dues à des contaminations et une prolifération bactérienne de germes aérobies ou anaérobies augmentée, ou de contamination par des protozoaires.  Digestive diseases, and more particularly those leading to diarrhea are very common diseases in humans and animals, especially in dogs and cats. These conditions are often due to contamination and increased bacterial proliferation of aerobic or anaerobic germs, or contamination by protozoa.
L'otite est une inflammation du conduit auditif. L'otite peut toucher toutes les espèces animales, ainsi que l'homme. Il s'agit d'une pathologie extrêmement fréquente chez les carnivores domestiques, en particulier le chien. Elle peut avoir de nombreuses origines dont certaines seront responsables d'otites récidivantes. Plusieurs types de bactéries (Staphylocoques, Pseudomonas...) et de levures (Malassezia) peuvent se développer dans le conduit auditif, provoquant l'apparition d'une otite. Ces otites sont alors associées à des sécrétions purulentes et à une odeur très désagréable. Otitis is an inflammation of the ear canal. Otitis can affect all animal species, as well as humans. It is an extremely common pathology in domestic carnivores, especially dogs. It can have many origins, some of which will be responsible for recurrent ear infections. Several types of Bacteria (Staphylococcus, Pseudomonas ...) and yeasts (Malassezia) can develop in the ear canal, causing the appearance of otitis. These ear infections are then associated with purulent secretions and a very unpleasant odor.
Selon un aspect particulier de l'invention, les composés de formule (I) sont administrés en combinaison avec un autre composé antibiotique, notamment de la famille des bêtalactamines (pénicillines / céphalosporines), aminosides, macrolides, polypeptides, sulfamides, quinolones, nitro-imidazolés, dérivés des nitrofuranes, dérivés du noyau benzyl-pyrimidine, des tétracyclines ou des phénicolés, tels que la doxycycline ou le chloramphénicol, la pénicilline, l'ampicilline, amoxicilline, la cloxacilline, la dicloxacilline, l'oxacilline, la nafcilline, la céfalexine, la céfapirine, la céfazoline, le ceftiofur, la céfopérazone, la céfovécine, le cefquinome, la thimaphénicol, le florfénicol, la terramycine, l'érythromycine, la spiramycine, la tylosine, la josamycine, le tilmicosine, la tulathromycine, la gamithromycine, la tildipirosine, la clyndamycine, la lyncomycine, la pirlymicine, le tiamuline, la valnémuline, l'acide oxolinique, la fluméquine, l'enrofloxacine, la danofloxacine, Pibafloxacine, la marbofloxacine, la difloxacine, l'obifloxacine, la pradofloxacine, la rifampicine, la rifaximine, le sulfaméthizol, la sulfathiazol, la sulfadimidine, la sulfaméthoxazole, la sulfadiazine, la sulfadiméthoxine, la sulfaméthoxypyridazine, le triméthoprime, la baquiloprime, le métronidazole, le dimétridazole, la ronidazole, la nitrofurantoïne, la furazolidone ou la furaltadone. Dans une utilisation particulièrement avantageuse des composés de l'invention, on observe une synergie lors de l'utilisation conjointe des composés de l'invention avec des antibiotiques.  According to one particular aspect of the invention, the compounds of formula (I) are administered in combination with another antibiotic compound, in particular of the family of beta-lactams (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulphonamides, quinolones, nitro- imidazoles, derivatives of nitrofurans, benzyl-pyrimidine ring derivatives, tetracyclines or phenicolates, such as doxycycline or chloramphenicol, penicillin, ampicillin, amoxicillin, cloxacillin, dicloxacillin, oxacillin, nafcillin, Cefalexin, cefapirin, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, thimaphenicol, florfenicol, terramycin, erythromycin, spiramycin, tylosin, josamycin, tilmicosin, tulathromycin, gamithromycin , tildipirosin, clyndamycin, lyncomycin, pirlymicin, tiamulin, valnemulin, oxolinic acid, flumequine, enrofloxacin, danofloxacin, bibafloxacin, marbofloxacin, difloxacin, obifloxacin, pradofloxacin, rifampicin, rifaximin, sulfamethizol, sulfathiazol, sulfadimidine, sulfamethoxazole, sulfadiazine, sulfadimethoxine, sulfamethoxypyridazine, trimethoprim, baquiloprim , metronidazole, dimetridazole, ronidazole, nitrofurantoin, furazolidone or furaltadone. In a particularly advantageous use of the compounds of the invention, synergism is observed when the compounds of the invention are used together with antibiotics.
En effet, il a été observé que lorsque les composés de formule (I) étaient associés à un autre composé antibiotique, par exemple la doxycycline, l'ampicilline, l'érythromycine ou le chloramphénicol sur une souche Gram-négative de Pseudonomas aeruginosa, une synergie était observée, ainsi qu'illustré à l'exemple 5 ci-dessus. Cette propriété permet par exemple de traiter efficacement des patients avec un taux moindre d'antibiotique, ce qui peut diminuer l'apparition de résistance aux antibiotiques.  Indeed, it has been observed that when the compounds of formula (I) were associated with another antibiotic compound, for example doxycycline, ampicillin, erythromycin or chloramphenicol on a Gram-negative strain of Pseudonomas aeruginosa, a synergy was observed, as illustrated in Example 5 above. This property makes it possible, for example, to effectively treat patients with a lower level of antibiotic, which may reduce the appearance of antibiotic resistance.
La présente invention concerne ainsi également des compositions pharmaceutiques ou vétérinaires comprenant au moins un composé choisi parmi les composés de formules (I), (la), (Ib), (le), (Id) et (le) telles que définies ci-dessus et les composés (1) à (56) tel que défini ci-dessus ou un sel pharmaceutiquement acceptable de celui-ci et au moins un antibiotique différent d'un composé précité, plus particulièrement tel que défini précédemment, et encore plus particulièrement la doxycycline. The present invention thus also relates to pharmaceutical or veterinary compositions comprising at least one compound chosen from the compounds of formulas (I), (Ia), (Ib), (Ie), (Id) and (Ie) as defined above. and compounds (1) to (56) as defined above or a pharmaceutically acceptable salt of it and at least one antibiotic different from a aforementioned compound, more particularly as defined above, and even more particularly doxycycline.
Selon un aspect de l'invention, les compositions pharmaceutiques ou vétérinaires comprennent en outre un deuxième composé antibiotique, notamment de la famille des bêtalactamines (pénicillines / céphalosporines), aminosides, macrolides, polypeptides, sulfamides, quinolones, nitro-imidazolés, dérivés des nitrofuranes, dérivés du noyau benzyl-pyrimidine, des tétracyclines ou des phénicolés.  According to one aspect of the invention, the pharmaceutical or veterinary compositions also comprise a second antibiotic compound, in particular of the beta-lactam family (penicillins / cephalosporins), aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitroimidazoles, derivatives of nitrofurans. derivatives of the benzyl-pyrimidine ring, tetracyclines or phenicolates.
La présente invention concerne en outre l'utilisation des composés de formule The present invention further relates to the use of compounds of formula
(I), (Γ), (la), (Ib), (le), (Id) ou (le) ou encore un composé de formule (1) à (56) ou l'un de ses sels pharmaceutiquement acceptables, pour potentialiser l'activité antibiotique de composés antibiotiques pouvant être choisis parmi les composés antibiotiques précédemment cités. (I), (Γ), (1a), (Ib), (Ic), (Id) or (Ic) or a compound of formula (1) to (56) or a pharmaceutically acceptable salt thereof, to potentiate the antibiotic activity of antibiotic compounds that can be selected from the antibiotic compounds mentioned above.
Les composés conformes à l'invention sont également des composés de choix en tant que substituts aux antibiotiques. Les composés selon l'invention permettent une excellente activité contre les bactéries, tout en évitant l'apparition de résistances, qui est un atout majeur tant le problème de l'apparition de résistances aux antibiotiques classiques est devenu un problème de santé publique. De par leur mécanisme d'action, différent de celui des antibiotiques, les composés de l'invention se présentent donc comme d'excellents substituts aux antibiotiques.  The compounds according to the invention are also compounds of choice as antibiotic substitutes. The compounds according to the invention allow an excellent activity against bacteria, while avoiding the appearance of resistance, which is a major advantage as the problem of the appearance of resistance to conventional antibiotics has become a public health problem. By their mechanism of action, different from that of antibiotics, the compounds of the invention are therefore excellent as alternatives to antibiotics.
Selon un autre aspect, les composés de formule (I), (Γ), (la), (Ib), (le) ou (Id), et plus particulièrement les composés (1) à (56) ou l'un de leurs sels pharmaceutiquement acceptables selon l'invention sont notamment utiles pour lutter contre les maladies fongiques.  In another aspect, the compounds of formula (I), (Γ), (Ia), (Ib), (Ie) or (Id), and more particularly compounds (1) to (56) or one of their pharmaceutically acceptable salts according to the invention are especially useful for combating fungal diseases.
Les maladies fongiques sont généralement désignées sous le nom de mycose. Il existe de nombreux types de mycoses, qui diffèrent par l'espèce fongique en cause, la localisation de l'infection, son caractère aigu ou chronique, le mode d'infection, etc. Ces maladies sont par exemple, la teigne, la candidose ou l'onixys, la blastomycose, l'asperigllose, la coccidioïdomycose, la cryptococcose, la sporotrichose. Elles peuvent toucher les hommes ou les animaux. Les traitements sont soit topiques locaux, soit par voie orale, selon la gravité et le type d'atteinte. Parmi les champignons fréquemment impliqués dans les mycoses, en particulier humaines, on retrouve principalement : - les « levures » (champignons ronds microscopiques), dont les Candida, les Cryptococcus, les Pityrosporum et les Pneumocystis, responsables respectivement des candidoses, des cryptococcoses, des pityrosporoses et de la pneumocystose, Fungal diseases are commonly referred to as mycosis. There are many types of mycosis, which differ in the fungal species involved, the location of the infection, its acute or chronic nature, the mode of infection, etc. These diseases are, for example, ringworm, candidiasis or onixys, blastomycosis, asperigllosis, coccidioidomycosis, cryptococcosis, sporotrichosis. They can affect humans or animals. Treatments are either local topical or oral, depending on the severity and type of involvement. Among the fungi frequently involved in fungal infections, especially human fungi, we find mainly: - "yeasts" (round microscopic fungi), including Candida, Cryptococcus, Pityrosporum and Pneumocystis, respectively responsible for candidiasis, cryptococcosis, pityrosporosis and pneumocystis,
- les champignons dits « filamenteux », dont les dermatophytes (en cause dans les dermatophytoses), les Aspergillus (provoquant les aspergilloses respiratoires), etc, et  the so-called "filamentous" fungi, including dermatophytes (involved in dermatophytosis), Aspergillus (causing respiratory aspergillosis), etc., and
- les champignons dimorphiques (histoplasmose). Les infections causées par les Candida représentent la principale cause des infections fongiques allant des infections légères de la peau ou des muqueuses aux infections graves affectant un organe. Les champignons de type Aspergillus, sont responsables de la plupart des infections après le Candida.  - dimorphic fungi (histoplasmosis). Candida infections are the leading cause of fungal infections ranging from mild infections of the skin or mucous membranes to serious organ infections. Aspergillus fungi are responsible for most infections after Candida.
Selon encore un autre aspect de l'invention, les compositions pharmaceutiques ou vétérinaires comprennent en outre un deuxième composé antiparasitaire, notamment antipaludéen.  According to yet another aspect of the invention, the pharmaceutical or veterinary compositions further comprise a second antiparasitic compound, in particular an antimalarial compound.
Selon un autre aspect, l'invention fournit des composés de formule (I), (F), (la), (Ib), (le), (Id) ou (le) ou encore un composé de formule (1) à (56) ou l'un de ses sels pharmaceutiquement acceptables, pour leur utilisation dans le traitement d'infections parasitaires ou virales, de l'homme ou de l'animal, telles que le paludisme, le virus de l'immunodéficience féline (FIV), la péritonite infectieuse féline (PIF), la toxoplasmose, la leishmaniose, l'echinococcose, l'ehrlichiose, l'hépatite de Rubarth, la leptospirose, la maladie de Carré, la parvovirose du chien, la piroplasmose, la toux de chenil ou coqueluche, la dirofîlariose, la leucose féline (FeLV), le coryza, le typhus ou encore la panleucopénie féline. Les composés selon l'invention peuvent également être utilisés en tant qu'agent antiviral.  According to another aspect, the invention provides compounds of formula (I), (F), (Ia), (Ib), (Ie), (Id) or (Ie) or a compound of formula (1) to (56) or a pharmaceutically acceptable salt thereof, for use in the treatment of parasitic or viral infections of humans or animals, such as malaria, feline immunodeficiency virus (FIV) Feline infectious peritonitis (FIP), toxoplasmosis, leishmaniasis, echinococcosis, ehrlichiosis, Rubarth hepatitis, leptospirosis, distemper, dog parvovirus, piroplasmosis, kennel cough or pertussis, diroflariosis, feline leukemia (FeLV), common cold, typhus or feline panleukopenia. The compounds according to the invention can also be used as antiviral agent.
Selon un aspect particulier, les composés de formule (I) sont administrés en combinaison avec un autre composé antipaludéen. Avantageusement, les composés de formule (I) permettent de potentialiser l'activité des composés antiparasitaires, notamment antipaludéen.  In a particular aspect, the compounds of formula (I) are administered in combination with another antimalarial compound. Advantageously, the compounds of formula (I) make it possible to potentiate the activity of the antiparasitic compounds, in particular antimalarial compounds.
La présente invention concerne en outre une méthode de traitement d'un homme ou d'un animal souffrant d'infections bactériennes, fongiques, virales ou parasitaires, qui comprend au moins une étape d'administration d'une quantité efficace d'un composé selon l'une quelconque des formules (I), (Γ), (la), (Ib), (le), (Id) ou (le) telles que définies ci-dessus et (1) à (56) ou l'un de ses sels pharmaceutiquement acceptables. The present invention further relates to a method of treating a human or animal suffering from bacterial, fungal, viral or parasitic infections, which comprises at least one step of administering an effective amount of a compound according to any one of formulas (I), (Γ), (Ia), (Ib), (Ic), (Id) or (Ic) as defined above and (1) to (56) or one of its pharmaceutically acceptable salts.
La présente invention concerne également des compositions pharmaceutiques ou vétérinaires comprenant au moins un composé choisi parmi les composés de formules (I), (la), (Ib), (le), (Id) et (le) telles que définies ci-dessus et les composés (1) à (56) tel que défini ci-dessus ou un sel pharmaceutiquement acceptable de celui-ci et un excipient pharmaceutiquement acceptable. The present invention also relates to pharmaceutical or veterinary compositions comprising at least one compound chosen from the compounds of formulas (I), (Ia), (Ib), (Ie), (Id) and (Ie) as defined above. and compounds (1) to (56) as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Les compositions pharmaceutiques ou vétérinaires selon l'invention peuvent être présentées sous des formes solides ou liquides, destinées par exemple à l'administration par voie parentérale (intraveineuse, intramusculaire, sous cutanée), orale, générale, locale, transmuqueuse, percutanée, cutanée, oculaire, pulmonaire ou topique.  The pharmaceutical or veterinary compositions according to the invention may be presented in solid or liquid forms, intended, for example, for parenteral (intravenous, intramuscular, subcutaneous), oral, general, local, transmucosal, percutaneous, cutaneous, ocular, pulmonary or topical.
Elles sont donc présentées sous forme de solutés ou de suspensions injectables ou flacons mono-doses ou multi-doses, sous forme de comprimés nus ou enrobés, de dragées, de capsules, de gélules, de pilules, de cachets, de poudres, de suppositoires ou capsules rectales, de granulés ou de solutions.  They are therefore presented in the form of injectable solutes or suspensions or single-dose or multi-dose vials, in the form of naked or coated tablets, coated tablets, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules, granules or solutions.
De façon avantageuse, le produit selon l'invention comprend également un ou plusieurs ingrédients additionnels bien connus de l'homme du métier tels que notamment, les agents liants, les agents de granulation, les lubrifiants, les colorants, les charges, les émulsifiants, les minéraux, les agents de pelliculage, les sels, les stabilisants, les tampons ou les vitamines. Les stabilisants comprennent les substances qui ont tendance à augmenter la durée de conservation de la composition tels que les conservateurs, les émulsifiants, les épaississants, les gaz d'emballage, les gélifiants, les humectants, les séquestrants, les synergistes ou les stabilisants.  Advantageously, the product according to the invention also comprises one or more additional ingredients well known to those skilled in the art such as in particular, binding agents, granulation agents, lubricants, dyes, fillers, emulsifiers, minerals, film-coating agents, salts, stabilizers, buffers or vitamins. Stabilizers include those substances which tend to increase the shelf life of the composition such as preservatives, emulsifiers, thickeners, packaging gases, gelling agents, humectants, sequestering agents, synergists or stabilizers.
Pour l'administration par voie orale, les excipients pouvant convenir peuvent être les dérivés de cellulose ou de cellulose microcristalline, les carbonates alcalino- terreux, le phosphate de magnésium, les amidons, les amidons modifiés, le lactose pour les formes solides.  For oral administration, suitable excipients may be cellulose or microcrystalline cellulose derivatives, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.
Pour l'usage injectable, la formulation pourra comprendre un solvant aqueux, un solvant organique ou le mélange des deux ou une huile végétale, un solvant organique ou le mélange des deux. Parmi les solvants aqueux, l'eau, les solutés aqueux, le sérum physiologique, les solutés isotoniques sont les excipients les plus souvent utilisés. Parmi les huiles végétales, on peut citer par exemple l'huile de palme, l'huile de maïs, l'huile de coton, l'huile de tournesol, l'huile d'arachide, l'huile d'olive, l'huile de soja, l'huile de carthame, l'huile de coprah, l'huile de sésame, ou parmi les huiles végétales semi- synthétiques obtenues par fractionnement et/ou hydrolyse et/ou estérification totale des huiles végétales naturelles comme par exemple les triglycérides d'acide gras issus d'huiles végétales, comme les triglycérides des acides caprylique, caprique, linoléïque, succinique (vendues sous les dénominations commerciales Miglyol® 810, 812, 818, 820, 829), les esters du propylène glycol et d'acide gras issus d'huile végétale comme les esters du propylène glycol et des acides caprylique et caprique (vendues sous les dénominations commerciales Miglyol® 840), ainsi que leur mélange, ainsi que des esters parmi lesquels la Triacétine (triacétatc de glycéryle) , l'oléate d'éthyle, par exemple. Parmi les solvants organiques, on peut citer par exemple l'alcool benzylique, l'éthanol, la N-méthyl pyrrolidone, le glycerol-formal, le glycofurol, le Diethylene glycol monoethyl ether, le propylène glycol, le polyéthylène glycol par exemple, le PEG300, le PEG 200 et le PEG 400. La sélection du véhicule est réalisée, de manière à former des solutions liquides, en fonction de sa capacité à dissoudre la substance active à température ambiante sans en modifier la structure chimique et la stabilité. Le véhicule choisi doit être biocompatible et adaptés à la voie injectable. Le véhicule sera choisi parmi les solvants polaires, les solvants apolaires aprotiques ou leur mélange. La composition injectable liquide pourra également comprendre au moins un antioxydant choisi parmi le butylhydroxyanisol (BHA), butylhydroxytoluène (BHT), la vitamine E et ses dérivés, le propylgallate et les mélanges de ceux-ci. For injectable use, the formulation may comprise an aqueous solvent, an organic solvent or a mixture of both or a vegetable oil, an organic solvent or a mixture of both. Of the aqueous solvents, water, aqueous solutes, physiological saline, isotonic solutes are the most commonly used excipients. From vegetable oils, for example, palm oil, corn oil, cottonseed oil, sunflower oil, peanut oil, olive oil, soya oil, safflower oil, coconut oil, sesame oil, or from semi-synthetic vegetable oils obtained by fractionation and / or hydrolysis and / or total esterification of natural vegetable oils such as, for example, triglycerides fatty acid derived from vegetable oils, such as triglycerides of caprylic acid, capric acid, linoleic acid, succinic acid (sold under the trade names Miglyol ® 810, 812, 818, 820, 829), the esters of propylene glycol and fatty acid derived from vegetable oil such as esters of propylene glycol and caprylic and capric acids (sold under the trade names Miglyol ® 840), as well as their mixture, as well as esters including triacetin (glyceryl triacetate), oleate ethyl, for example. Among the organic solvents, mention may be made, for example, of benzyl alcohol, ethanol, N-methyl pyrrolidone, glycerol-formal, glycofurol, diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol for example, PEG300, PEG 200 and PEG 400. The selection of the vehicle is carried out so as to form liquid solutions, according to its ability to dissolve the active substance at room temperature without modifying its chemical structure and stability. The chosen vehicle must be biocompatible and adapted to the injectable route. The vehicle will be chosen from polar solvents, aprotic apolar solvents or their mixture. The liquid injectable composition may also comprise at least one antioxidant chosen from butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), vitamin E and its derivatives, propylgallate and mixtures thereof.
Pour une administration par voie transmuqueuse, notamment rectale, le beurre de cacao ou les stéarates de polyéthylèneglycol sont les excipients préférés.  For transmucosal administration, especially rectal administration, cocoa butter or polyethylene glycol stearates are the preferred excipients.
Pour l'usage percutané ou cutané, notamment sur la peau, les muqueuses ou le poil, en particulier pour les solutions à verser de type « pour-on » ou « spot-on » en médecine vétérinaire, les excipients usuels sont des solvants aqueux, alcooliques, polaire ou non, qui favorisent le passage transcutané, tel que l'eau, l'alcool benzylique, les huiles végétales et minérales, les agents de remise en suspension, les antioxydants, les tensioactifs, notamment un mélange constitué d'alcool benzylique et/ou de labrasol et/ou de laurate de propylène glycol, à titre d'agent de pénétration peut être utilisé. Pour une utilisation oculaire, les excipients adéquats pourront également être sélectionnés par l'homme du métier en fonction des spécificités requises. For percutaneous or cutaneous use, in particular on the skin, the mucous membranes or the hair, in particular for "pour-on" or "spot-on" solutions in veterinary medicine, the usual excipients are aqueous solvents , alcoholic, polar or otherwise, which promote transcutaneous passage, such as water, benzyl alcohol, vegetable and mineral oils, resuspension agents, antioxidants, surfactants, including a mixture of alcohol benzyl and / or labrasol and / or propylene glycol laurate as a penetrating agent may be used. For ocular use, the appropriate excipients may also be selected by those skilled in the art depending on the specificities required.
La posologie peut varier dans les limites importantes (0,05 mg à 1000 mg) en fonction de l'indication thérapeutique et de la voie d'administration, ainsi que de l'âge et du poids du sujet.  The dosage may vary within the important limits (0.05 mg to 1000 mg) depending on the therapeutic indication and the route of administration, as well as the age and weight of the subject.
D'autres utilisations des composés de l'invention sont envisagées, par exemple en tant qu'agent de restriction des contaminations, telle que la formulation dans une pommade nasale.  Other uses of the compounds of the invention are contemplated, for example as a restriction agent for contaminations, such as the formulation in a nasal ointment.
La présente invention concerne également l'utilisation d'au moins un composé choisi parmi un composé de l'une quelconque des formules (I), (I '), (la), (Ib), (le), (Id) et (le) telles que définies ci-dessus, et les composés (1) à (56) tels que définis ci-dessus, ou un de ses sels pharmaceutiquement acceptables selon la présente invention pour la fabrication d'une composition pharmaceutique ou vétérinaire destinée à la prévention et/ou au traitement d'un infection bactérienne, fongique, virale ou parasitaire. The present invention also relates to the use of at least one compound selected from a compound of any one of formulas (I), (I '), (Ia), (Ib), (Ie), (Id) and (le) as defined above, and the compounds (1) to (56) as defined above, or a pharmaceutically acceptable salt thereof according to the present invention for the manufacture of a pharmaceutical or veterinary composition intended for the prevention and / or treatment of a bacterial, fungal, viral or parasitic infection.

Claims

REVENDICATIONS
1. Composé de formule (I) 1. Compound of formula (I)
Figure imgf000067_0001
Figure imgf000067_0001
dans laquelle  in which
RI et R2 représentent indépendamment un atome d'hydrogène, un groupe SO3H ou un groupe hydroxy,  R1 and R2 independently represent a hydrogen atom, a SO3H group or a hydroxy group,
R' représente un groupe -(CRaRb)n-X-(CRcRd)m-[Y-(CReRf)o]t-NR9Rio, R 'represents a group - (CRaRb) n-X- (CRcRd) m- [Y- (CReRf) o] t -NR9Rio,
Ra, Rb, Rc, Rd, Re et Rf représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe (C6-Cio)aryle, Ra, Rb, Rc, Rd, Re and Rf independently represent a hydrogen atom, a (Ci-Cs) alkyl group or a (C 6 -Cio) aryl group,
X et Y représentent indépendamment un groupe -NR1 1-, un groupe -O- ou un groupe hétérocyclique divalent comprenant au moins un atome d'azote, à 5 ou 6 chaînons,  X and Y independently represent a group -NR1 1-, a group -O- or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members,
R9 et RIO représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou forment ensemble, avec l'atome d'azote qui les porte, un groupe hétérocyclique à 5 ou 6 chaînons, éventuellement substitué par un ou deux groupe(s) =0 ou =S,  R 9 and R 10 independently represent a hydrogen atom, a (C 1 -C 5) alkyl group or together with the nitrogen atom which carries them a 5- or 6-membered heterocyclic group, optionally substituted by one or two groups (s) = 0 or = S,
Rl l représente un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe -(CH2)S-NH2, R 1 represents a hydrogen atom, a (C 1 -C 5) alkyl group or a - (CH 2 ) S -NH 2 group ,
RI 5 et RI 6 représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe (C6-Cio)aryle, RI 5 and RI 6 independently represent a hydrogen atom, a (C 1 -C 5) alkyl group or a (C 6 -C 10) aryl group,
n, m, o et s représentent indépendamment un nombre entier compris entre 1 et 5,  n, m, o and s independently represent an integer from 1 to 5,
t est égal à 0, 1 , 2 ou 3,  t is 0, 1, 2 or 3,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci.  as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
2. Composé selon la revendication 1 , caractérisé en ce qu'il est défini par au moins l'un des sous-groupes suivants : - premier sous-groupe de composés de formule (I) lesquels RI et R2 représentent indépendamment un atome d'hydrogène ou un groupe hydroxy, 2. Compound according to claim 1, characterized in that it is defined by at least one of the following subgroups: - first subgroup of compounds of formula (I) which RI and R2 independently represent a hydrogen atom or a hydroxy group,
- deuxième sous-groupe de composés de formule (I) pour lesquels RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C4)alkyle,  second subgroup of compounds of formula (I) for which R 1 and R 6 independently represent a hydrogen atom or a (C 1 -C 4) alkyl group,
- troisième sous-groupe de composés de formule (I) pour lesquels X est un groupe -NH-, un groupe hétérocyclique à 6 chaînons comportant un ou deux atomes d'azote, de préférence un groupe 1 ,4-pipérazinylene ou un groupe 1,4-pipéridinylene,  third subgroup of compounds of formula (I) for which X is a group -NH-, a 6-membered heterocyclic group containing one or two nitrogen atoms, preferably a 1,4-piperazinylene group or a group 1 , 4-piperidinylene,
- quatrième sous-groupe de composés de formule (I) pour lesquels R9 et RIO représentent un atome d'hydrogène,  fourth subgroup of compounds of formula (I) for which R 9 and R 10 represent a hydrogen atom,
- cinquième sous-groupe de composés de formule (I) pour lesquels Ra, Rb, Rc, fifth subgroup of compounds of formula (I) for which Ra, Rb, Rc,
Rd, Re et Rf représentent un atome d'hydrogène, Rd, Re and Rf represent a hydrogen atom,
- sixième sous-groupe de composés de formule (I) pour lesquels Y est un groupe -NR11-, avec RI 1 représentant un atome d'hydrogène, un groupe (Ci-C4)alkyle ou un groupe -(CH2)s-NH2 où s est égal à 1, 2 ou 3, sixth subset of compounds of formula (I) for which Y is a group -NR 11 -, with R 1 representing a hydrogen atom, a (C 1 -C 4) alkyl group or a - (CH 2 ) s group; NH 2 where s is 1, 2 or 3,
- septième sous-groupe de composés de formule (I) pour lesquels m est égal à - seventh subgroup of compounds of formula (I) for which m is equal to
2, 3, 4, ou 5, plus préférentiellement à 2 ou 3, 2, 3, 4, or 5, more preferably 2 or 3,
- huitième sous-groupe de composés de formule (I) pour lesquels n est égal à 2, eighth subgroup of compounds of formula (I) for which n is equal to 2,
3, 4 ou 5, plus préférentiellement à 2, 3 ou 4, 3, 4 or 5, more preferably 2, 3 or 4,
- neuvième sous-groupe de composés de formule (I) pour lesquels m est différente de 4,  ninth subgroup of compounds of formula (I) for which m is not equal to 4,
- dixième sous-groupe de composés de formule (I) pour lesquels o est égal à 2 ou 3,  tenth subgroup of compounds of formula (I) for which o is 2 or 3,
- onzième sous-groupe de composés de formule (I) pour lesquels le groupe - NHR' est choisi parmi : eleventh subgroup of compounds of formula (I) for which the group - NHR 'is chosen from:
Figure imgf000069_0001
Figure imgf000069_0001
dans laquelle  in which
RI et R2 sont tels que définis en revendication 1 ou 2,  R1 and R2 are as defined in claim 1 or 2,
RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C8)alkyle, RI 5 and RI 6 independently represent a hydrogen atom or a (C 1 -C 8 ) alkyl group,
n représente le nombre entier 2, 3 ou 4,  n represents the integer 2, 3 or 4,
m représente le nombre entier 2, 3 ou 4, X représente un groupe -NRl l- ou un groupe hétérocyclique divalent comprenant un ou deux atomes d'azote, à 5 ou 6 chaînons, tel qu'un groupe 1 ,4-pipérazinylene ou un groupe 1 ,4-pipéridinylene, m represents the integer 2, 3 or 4, X represents a group -NR1 1- or a divalent heterocyclic group comprising one or two nitrogen atoms, with 5 or 6 members, such as a 1,4-piperazinylene group or a 1,4-piperidinylene group,
R4 et Rl l représentent indépendamment un atome d'hydrogène, un groupe (Ci-Cs)alkyle ou un groupe -(CH2)s-NH2, R 4 and R s independently represent a hydrogen atom or a (Ci-Cs) alkyl or a group - (CH 2) s NH 2,
R5 représente un atome d'hydrogène, un groupe -(CH2)P-NH2, un groupe -(CH2)p-NH-(CH2)q-NH2 ou un groupe -(CH2)p-NH-(CH2)q-NH-(CH2)r-NH2, p, q, r et s représentent indépendamment un nombre entier pouvant varier entre 1 et 5, R5 represents a hydrogen atom, a - (CH 2 ) p -NH 2 group, a - (CH 2 ) p -NH- (CH 2 ) q -NH 2 group or a - (CH 2 ) p-NH- (CH 2) q -NH- (CH 2 ) r -NH 2, p, q, r and s independently represent an integer ranging from 1 to 5,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci.  as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
4. Composé selon l'une quelconque des revendications 1 à 3, caractérisé en ce que RI 5 et RI 6 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C4)alkyle tel qu'un méthyle ou un isoproyle.  4. Compound according to any one of claims 1 to 3, characterized in that RI 5 and RI 6 independently represent a hydrogen atom or a group (C 1 -C 4) alkyl such as methyl or isoproyl.
5. Composé selon l'une quelconque des revendications 1 à 4, caractérisé en ce que n est égal à 2 et m est égal à 3, n est égal à 2 et m est égal à 2, n est égale à 3 et m est égal à 4 ou bien n est égal à 3 et m est égal à 3.  5. Compound according to any one of claims 1 to 4, characterized in that n is 2 and m is 3, n is 2 and m is 2, n is 3 and m is equal to 4 or n is equal to 3 and m is equal to 3.
6. Composé selon l'une quelconque des revendications 3 à 5, caractérisé en ce que X représente un groupe -NRl l- ou un groupe 1 ,4-pipérazinylene et R4 et Rl l représentant indépendamment un atome d'hydrogène, un groupe méthyle ou un groupe -(CH2)S-NH2, dans lequel s est égal à 2 ou 3. 6. A compound according to any one of claims 3 to 5, characterized in that X represents a group -NR1 1- or a group 1, 4-piperazinylene and R4 and R11 independently represent a hydrogen atom, a methyl group or a group - (CH 2 ) S -NH 2 , wherein s is 2 or 3.
7. Composé selon l'une quelconque des revendications 3 à 5, caractérisé en ce que R5 représente un atome d'hydrogène, un groupe -(CH2)P-NH2, un groupe -(CH2)p-NH-(CH2)q-NH2 ou un groupe -(CH2)p-NH-(CH2)q-NH-(CH2)r-NH2, avec p est égal à 2 ou 3, q est égal à 2 et r est égal à 2. 7. Compound according to any one of claims 3 to 5, characterized in that R5 represents a hydrogen atom, a - (CH 2 ) p -NH 2 group, a - (CH 2 ) p -NH- group ( CH 2 ) q -NH 2 or a group - (CH 2 ) p -NH- (CH 2 ) q -NH- (CH 2 ) r -NH 2, where p is 2 or 3, q is 2 and r is equal to 2.
8. Composé selon l'une quelconque des précédentes revendications, caractérisé en ce qu'il représente alternativement  8. Compound according to any one of the preceding claims, characterized in that it represents alternately
- la formule (la)
Figure imgf000071_0001
- the formula (la)
Figure imgf000071_0001
dans laquelle in which
RI 5, RI 6, RI et R2 sont tels que définis dans l'une quelconque des revendications 3 à 5,  RI 5, RI 6, RI and R2 are as defined in any one of claims 3 to 5,
X représente un groupe -NH- ou un groupe 1 ,4-pipérazinylene,  X represents an -NH- group or a 1,4-piperazinylene group,
R5 représente un atome d'hydrogène ou un groupe -(CH2)P-NH2, avec p est égal à 2 ou 3, R5 represents a hydrogen atom or a - (CH 2 ) p -NH 2 group , with p is equal to 2 or 3,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof,
- la formule (Ib) - the formula (Ib)
Figure imgf000071_0002
(Ib) dans laquelle
Figure imgf000071_0002
(Ib) in which
RI 5, RI 6, RI et R2 sont tels que définis dans l'une quelconque des revendications 3 à 5,  RI 5, RI 6, RI and R2 are as defined in any one of claims 3 to 5,
u est égal à 0, 1, 2 ou 3, préférentiellement à 1, 2 ou 3, u is 0, 1, 2 or 3, preferably 1, 2 or 3,
R6 et R7 représentent indépendamment un atome d'hydrogène ou un groupe (Ci-C8)alkyle, de préférence un atome d'hydrogène ou un groupe (Ci-C4)alkyle, R6 and R7 independently represent a hydrogen atom or a (Ci-C8) alkyl, preferably a hydrogen atom or a (Ci-C 4) alkyl,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof,
- la formule (le)
Figure imgf000072_0001
- the formula
Figure imgf000072_0001
dans laquelle in which
RI 5, RI 6, RI, R2, n et m sont tels que définis dans l'une quelconque des revendications 3 à 5, et  RI 5, RI 6, RI, R2, n and m are as defined in any one of claims 3 to 5, and
R8 représente un groupe (Ci-C8)alkyle, de préférence un groupe méthyle, ou un groupe -(CH2)s-NH2, avec s étant un nombre entier pouvant varier entre 1 et 5, de préférence égal à 2 ou 3, R 8 represents a (C 1 -C 8) alkyl group, preferably a methyl group, or a - (CH 2 ) s -NH 2 group , where s is an integer ranging from 1 to 5, preferably 2 or 3 ,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof,
- la formule (Id) - the formula (Id)
Figure imgf000072_0002
Figure imgf000072_0002
dans laquelle in which
RI 5, RI 6, RI et R2 sont tels que définis dans l'une quelconque des revendications 3 à 5,  RI 5, RI 6, RI and R2 are as defined in any one of claims 3 to 5,
R5 représente un groupe -(CH2)P-NH2, avec p est égal à 2 ou 3, R5 is - (CH 2 ) p -NH 2 , where p is 2 or 3,
ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci, ou as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof, or
- la formule (le)
Figure imgf000073_0001
- the formula
Figure imgf000073_0001
dans laquelle  in which
R15, R16, RI et R2 sont tels que définis selon l'une quelconque des revendications 3 à 5,  R15, R16, R1 and R2 are as defined in any one of claims 3 to 5,
R5 représente un groupe -(CH2)p-NH2, avec p est égal à 2 ou 3, ainsi que les stéréoisomères, mélanges de stéréoisomères, et/ou sels pharmaceutiquement acceptables de celui-ci. R5 represents a - (CH 2 ) p -NH 2 group , with p is 2 or 3, as well as stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof.
9. Composé de formule (I) tel que défini à la revendication 1 choisi parmi les composés suivants :  9. Compound of formula (I) as defined in claim 1 selected from the following compounds:
- (1) 3P-norspermino-N-isopropyl-désoxycholamide,  - (1) 3β-Norspermino-N-isopropyl-deoxycholamide,
- (2) 3P-norspermidino-N-isopropyl-désoxycholamide,  - (2) 3β-Norspermidino-N-isopropyl-deoxycholamide,
- (3) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide, - (3) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-deoxycholamide,
- (4) 3P-norspermino-N-isopropyl-cholamide, (4) 3β-Norspermino-N-isopropylcholamide,
- (5) 3P-norspermidino-N-isopropyl-cholamide,  - (5) 3β-Norspermidino-N-isopropylcholamide,
- (6) 3P-(l,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxycholamide, (6) 3β- (1,4-bis (3-aminopropyl) piperazine) -N-isopropyl-deoxycholamide,
- (7) 3P-norspermino-N-isopropyl-chénodésoxycholamide, - (7) 3β-Norspermino-N-isopropyl-chenodeoxycholamide,
- (8) 3P-norspermidino-N-isopropyl-chénodésoxycholamide,  - (8) 3β-Norspermidino-N-isopropyl-chenodeoxycholamide,
- (9) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-chénodésoxy cholamide,  (9) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-chenodeoxy cholamide,
- (10) 3P-norspermino-N-méthyl-chénodésoxycholamide,  - (10) 3β-Norspermino-N-methyl-chenodeoxycholamide,
- (11) 3P-norspermidino-N-méthyl-chénodésoxycholamide,  - (11) 3β-Norspermidino-N-methyl-chenodeoxycholamide,
- (12) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-méthyl-chénodésoxy cholamide,  - (12) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-methyl-chenodeoxy cholamide,
- (13) 3P-norspermidino- N,N-diéthyl-chénodésoxycholamide,  (13) 3β-Norspermidino-N, N-diethyl-chenodeoxycholamide,
- (14) 3P-norspermino-N-isopropyl-ursodésoxycholamide,  - (14) 3β-Norspermino-N-isopropyl ursodeoxycholamide,
- (15) 3P-norspermidino-N-isopropyl-ursodésoxycholamide,  - (15) 3β-Norspermidino-N-isopropyl ursodeoxycholamide,
- (16) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-ursodésoxy cho lamide, - (16) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl ursodeoxy cho lamide,
- (17) 3P-norspermino-N-isopropyl-lithocholamide,  - (17) 3 P-norspermino-N-isopropyl-lithocholamide,
- (18) 3P-norspermidino-N-isopropyl-lithocholamide,  - (18) 3 P-norspermidino-N-isopropyl-lithocholamide,
- (19) 3β-(1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-lithocho lamide, (19) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-lithocholamide,
- (20) 3 P-(pentaéthylènehexamine)-N-isopropyl-désoxy cho lamide, - (20) 3 P- (pentaethylenehexamine) -N-isopropyl-deoxycholamide,
- (21) 3P-(pentaéthylènehexamine)-N-isopropyl-cholamide,  - (21) 3 P- (pentaethylenehexamine) -N-isopropylcholamide,
- (22) 3 P-(pentaéthylènehexamine)-N-isopropyl-chénodésoxycho lamide, (22) 3 P- (pentaethylenehexamine) -N-isopropyl-chenodeoxycholamide,
- (23) 3 P-(pentaéthylènehexamine)-N-isopropyl-ursodésoxycho lamide, (23) 3 P- (pentaethylenehexamine) -N-isopropyl ursodeoxycholamide,
- (24) N-isopropyl-3P-pentaéthylènehexamine-désoxycho lamide,  - (24) N-isopropyl-3β-pentaethylenehexamine-deoxycholamide,
- (25) 3 β-( 1 ,4-Bis(3-aminopropyl)pipérazine)-N-isopropyl-désoxy cho lamide, - (25) 3β- (1,4-Bis (3-aminopropyl) piperazine) -N-isopropyl-deoxycholamide,
- (26) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-cho lamide, - (26) 3 P- (bis (3-aminopropyl) methylamine) -N-isopropylcholamide,
- (27) 3P-(Bis(3-aminopropyl)méthylamine)-N-isopropyl-chénodésoxy cho lamide,  (27) 3β- (Bis (3-aminopropyl) methylamine) -N-isopropyl-chenodeoxycholamide,
- (28) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-ursodésoxy cho lamide,  - (28) 3 P- (Bis (3-aminopropyl) methylamine) -N-isopropyl ursodeoxy chloramide,
- (29) 3 P-(Bis(3 -aminopropyl)méthylamine)-N-isopropyl-lithocho lamide, (29) 3 P- (bis (3-aminopropyl) methylamine) -N-isopropyl-lithocholamide,
- (30) 3 β-spermino-N-isopropyl-désoxycho lamide, - (30) 3β-spermino-N-isopropyl-deoxycholamide,
- (31) 3P-spermino-N-isopropyl-cholamide,  - (31) 3β-spermino-N-isopropylcholamide,
- (32) 3P-spermino-N-isopropyl-chénodésoxycholamide,  - (32) 3β-Spermino-N-isopropyl-chenodeoxycholamide,
- (33) 3 β-spermino-N-méthyl-désoxycho lamide,  - (33) 3β-spermino-N-methyl-deoxycholamide,
- (34) 3P-spermino-N,N-diéthyl-chénodésoxycholamide,  - (34) 3β-spermino-N, N-diethyl-chenodeoxycholamide,
- (35) 3 β-spermino-N-isopropyl-ursodésoxycho lamide,  - (35) 3β-spermino-N-isopropyl ursodeoxycholamide,
- (36) 3P-spermino-N-isopropyl-lithocholamide,  - (36) 3β-spermino-N-isopropyl-lithocholamide,
- (37) 3P-norspermidino-N-diisopropyl-chénodésoxycholamide,  - (37) 3β-Norspermidino-N-diisopropyl-chenodeoxycholamide,
- (38) 3P-norspermidino-N-cyclohexyl-chénodésoxycholamide,  - (38) 3β-Norspermidino-N-cyclohexyl-chenodeoxycholamide,
- (39) 3P-norspermino-N,N-diéthyl-chénodésoxycholamide,  - (39) 3β-Norspermino-N, N-diethyl-chenodeoxycholamide,
- (40) 3P-norspermino-N,N- diisopropyl-chénodésoxycholamide,  - (40) 3β-Norspermino-N, N-diisopropyl-chenodeoxycholamide,
- (42) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-désoxycho lamide,  (42) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl-deoxycholamide,
- (43) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-cho lamide,  (43) 3 P- (Tris (3-aminopropyl) amine) -N-isopropylcholamide,
- (44) 3 P-(Tris(3 -aminopropyl)amine)-N,N-diéthyl-chénodésoxycho lamide, - (44) 3 P- (Tris (3-aminopropyl) amine) -N, N-diethyl-chenodeoxycholamide,
- (45) 3 P-(Tris(2-amino éthyl)amine)-N-isopropyl-chénodésoxycho lamide,- (45) 3 P- (Tris (2-aminoethyl) amine) -N-isopropyl-chenodeoxycholamide,
- (46) 3 P-(Tris(3-aminopropyl)amine)-N-isopropyl-chénodésoxycho lamide, - (47) 3P-(Tris(3-aminopropyl)amine)-N-cyclohexyl-chénodésoxycholamide,- (46) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl-chenodeoxycholamide, (47) 3 P- (Tris (3-aminopropyl) amine) -N-cyclohexyl-chenodeoxycholamide,
- (48) 3P-(Tris(3-aminopropyl)amine)-N-isopropyl-ursodésoxycholamide,- (48) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl ursodeoxycholamide,
- (49) 3 P-(Tris(3 -aminopropyl)amine)-N-isopropyl-lithocho lamide,- (49) 3 P- (Tris (3-aminopropyl) amine) -N-isopropyl-lithocholamide,
- (50) 3P-spermino-N,N-diisopropyl-chénodésoxycholamide, - (50) 3β-spermino-N, N-diisopropyl-chenodeoxycholamide,
- (51) 3P-spermino-N-cyclohexyl-chénodésoxycholamide,  - (51) 3β-spermino-N-cyclohexyl-chenodeoxycholamide,
- (52) 3 β-spermidino-N-isopropyl-chénodésoxycho lamide,  - (52) 3β-spermidino-N-isopropyl-chenodeoxycholamide,
- (53) 3P-(Bis(3-aminopropyl)éthylènediamine)-N,N-diéthyl-chénodésoxy cho lamide,  (53) 3 P- (Bis (3-aminopropyl) ethylenediamine) -N, N-diethyl-chenodeoxycholamide,
- (54) 3P-(Bis(3-aminopropyl)éthylènediamine)-N,N-diisopropyl-chénodésoxy cho lamide,  (54) 3 P- (Bis (3-aminopropyl) ethylenediamine) -N, N-diisopropyl-chenodeoxycholamide,
- (55) Mélange 50/50 de 3P-spermidino-N-isopropyl-chénodésoxycholamide et de 3P-N-[4'N-(3'-aminopropyl)aminobutyl]amino-N-isopropyl-chénodésoxycho lamide,  (55) 50/50 mixture of 3β-spermidino-N-isopropyl-chenodeoxycholamide and 3β-N- [4'N- (3'-aminopropyl) aminobutyl] amino-N-isopropyl-chenodeoxycholamide,
- (56) 3P-(Tris(3-aminopropyl)amine)-N,N- diisopropyl-chénodésoxy cho lamide,  (56) 3 P- (Tris (3-aminopropyl) amine) -N, N-diisopropyl-chenodeoxycholamide,
ou l'un de ses sels pharmaceutiquement acceptables, et plus particulièrement choisis parmi les composés (1), (2), (5), (13), (15), (33) et (34).  or a pharmaceutically acceptable salt thereof, and more particularly chosen from compounds (1), (2), (5), (13), (15), (33) and (34).
10. Composé de formule (I) selon l'une quelconque des revendications précédentes, pour son utilisation à titre de médicament.  10. Compound of formula (I) according to any one of the preceding claims, for its use as a medicament.
11. Composition pharmaceutique ou vétérinaire comprenant un composé de formule (I) tel que défini dans l'une quelconque des revendications 1 à 9 et un excipient pharmaceutiquement acceptable.  11. A pharmaceutical or veterinary composition comprising a compound of formula (I) as defined in any one of claims 1 to 9 and a pharmaceutically acceptable excipient.
12. Compositions pharmaceutiques ou vétérinaires comprenant au moins un composé de formule (I) tel que défini dans l'une quelconque des revendications 1 à 9 et au moins un antibiotique, différent d'un tel composé de formule (I), plus particulièrement de la famille des bêtalactamines, aminosides, macrolides, polypeptides, sulfamides, quinolones, nitro-imidazolés, dérivés des nitrofuranes, dérivés du noyau benzyl- pyrimidine, des tétracyclines ou des phénicolés, tels que la doxycycline ou le chloramphénicol, la pénicilline, l'ampicilline, amoxicilline, la cloxacilline, la dicloxacilline, l'oxacilline, la nafcilline, la céfalexine, la céfapirine, la céfazoline, le ceftiofur, la céfopérazone, la céfovécine, le cefquinome, la thimaphénicol, le f orfénicol, la terramycine, l'érythromycine, la spiramycine, la tylosine, la josamycine, le tilmicosine, la tulathromycine, la gamithromycine, la tildipirosine, la clyndamycine, la lyncomycine, la pirlymicine, le tiamuline, la valnémuline, l'acide oxo Unique, la fluméquine, l'enrofloxacine, la danofloxacine, Pibafloxacine, la marbofloxacine, la difloxacine, l'obifloxacine, la pradofloxacine, la rifampicine, la rifaximine, le sulfaméthizol, la sulfathiazol, la sulfadimidine, la sulfaméthoxazole, la sulfadiazine, la sulfadiméthoxine, la sulfaméthoxypyridazine, le triméthoprime, la baquiloprime, le métronidazole, le dimétridazole, la ronidazole, la nitrofurantoïne, la furazolidone ou la furaltadone, et encore plus particulièrement la doxycycline, Pampicilline, l'érythromycine ou le chloramphénicol. 12. Pharmaceutical or veterinary compositions comprising at least one compound of formula (I) as defined in any one of claims 1 to 9 and at least one antibiotic, different from such a compound of formula (I), more particularly from the family of beta-lactams, aminoglycosides, macrolides, polypeptides, sulfonamides, quinolones, nitroimidazoles, derivatives of nitrofurans, benzylpyrimidine ring derivatives, tetracyclines or phenicolates, such as doxycycline or chloramphenicol, penicillin, ampicillin amoxicillin, cloxacillin, dicloxacillin, oxacillin, nafcillin, cefalexin, cefapirin, cefazolin, ceftiofur, cefoperazone, cefovecin, cefquinome, thimaphenicol, f orfenicol, terramycin, erythromycin , spiramycin, tylosin, josamycin, tilmicosin, tulathromycin, gamithromycin, tildipirosin, clyndamycin, lyncomycin, pirlymicin, tiamulin, valnemulin, single oxo acid, flumequine, enrofloxacin, danofloxacin, bibafloxacin, marbofloxacin, difloxacin, obifloxacin, pradofloxacin, rifampicin, rifaximin, sulfamethizol, sulfathiazole sulfadimidine, sulfamethoxazole, sulfadiazine, sulfadimethoxine, sulfamethoxypyridazine, trimethoprim, baquiloprime, metronidazole, dimetridazole, ronidazole, nitrofurantoin, furazolidone or furaltadone, and even more particularly doxycycline, ampicillin, Erythromycin or chloramphenicol.
13. Composé selon l'une quelconque des revendications 1 à 9 pour son utilisation pour prévenir et/ou inhiber et ou traiter les infections bactériennes, fongiques, virales ou parasitaires chez l'homme ou l'animal.  13. A compound according to any one of claims 1 to 9 for use in preventing and / or inhibiting and or treating bacterial, fungal, viral or parasitic infections in humans or animals.
14. Utilisation d'un composé selon l'une quelconque des revendications 1 à 9, pour potentialiser l'activité antibiotique de composés antibiotiques pouvant être choisis parmi les composés antibiotiques tels que décrits en revendication 12.  14. Use of a compound according to any one of claims 1 to 9 for potentiating the antibiotic activity of antibiotic compounds which may be selected from antibiotic compounds as described in claim 12.
15. Procédé de préparation d'un composé de formule (I) tels que définis à l'une quelconque des revendications 1 à 9, comprenant une étape d'amination réductrice du composé de formule (II)  15. Process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 9, comprising a step of reductive amination of the compound of formula (II)
Figure imgf000076_0001
Figure imgf000076_0001
dans laquelle R15, R16, RI et R2 sont tels que définis dans l'une des revendications 1, 2 ou 3,  wherein R15, R16, R1 and R2 are as defined in one of claims 1, 2 or 3,
avec une aminé de formule R'NH2, dans laquelle R' est telle que définie dans la revendication 1, en présence d'un agent réducteur pouvant être choisi parmi le tétraisopropylate de titane, le tétraisopropylate de zirconium, le NaBH3CN, le NaBH4, ou d'un mélange d'entre eux, préférentiellement le couple tétraisopropylate de titane/NaBH4, pour obtenir ledit composé de formule (I). with an amine of formula R'NH2, in which R 'is as defined in claim 1, in the presence of a reducing agent that may be selected from titanium tetraisopropylate, zirconium tetraisopropylate, NaBH 3 CN, NaBH 4 , or a mixture of them, preferably the tetraisopropylate pair of titanium / NaBH 4 , to obtain said compound of formula (I).
PCT/EP2017/073267 2016-09-15 2017-09-15 Amide derivatives of squalamine for the treatment of infections WO2018050815A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP17764847.4A EP3512864B1 (en) 2016-09-15 2017-09-15 Amide derivatives of squalamine for the treatment of infections
US16/333,484 US10780101B2 (en) 2016-09-15 2017-09-15 Amide derivatives of squalamine for the treatment of infections
CN201780057107.1A CN109996804B (en) 2016-09-15 2017-09-15 Squalamine amide derivatives for the treatment of infections

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1658650 2016-09-15
FR1658650A FR3055802B1 (en) 2016-09-15 2016-09-15 SQUALAMINE AMIDE DERIVATIVES FOR THE TREATMENT OF INFECTIONS

Publications (1)

Publication Number Publication Date
WO2018050815A1 true WO2018050815A1 (en) 2018-03-22

Family

ID=57485672

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/073267 WO2018050815A1 (en) 2016-09-15 2017-09-15 Amide derivatives of squalamine for the treatment of infections

Country Status (5)

Country Link
US (1) US10780101B2 (en)
EP (1) EP3512864B1 (en)
CN (1) CN109996804B (en)
FR (1) FR3055802B1 (en)
WO (1) WO2018050815A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023208988A1 (en) * 2022-04-26 2023-11-02 Université D'aix-Marseille Antibacterial compounds eliminating dormant bacterial cells

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856535A (en) 1994-08-18 1999-01-05 Magainin Pharmaceuticals, Inc. Aminosterol ester compounds
WO2011067501A1 (en) 2009-12-02 2011-06-09 Assistance Publique - Hopitaux De Marseille Local topical application aminosteroid compounds for mucous/cutaneous decolonization of staphylococcus aureus

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856535A (en) 1994-08-18 1999-01-05 Magainin Pharmaceuticals, Inc. Aminosterol ester compounds
WO2011067501A1 (en) 2009-12-02 2011-06-09 Assistance Publique - Hopitaux De Marseille Local topical application aminosteroid compounds for mucous/cutaneous decolonization of staphylococcus aureus

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Larock dans Comprehensive Organic Transformations", 1989, VCH PUB.
A. M. BELLINI ET AL: "Antimicrobial Activity of Basic Cholane Derivatives Part IX", ARCHIV DER PHARMAZIE, vol. 323, no. 4, 1 January 1990 (1990-01-01), pages 201 - 205, XP055024553, ISSN: 0365-6233, DOI: 10.1002/ardp.19903230404 *
AM BELLINI ET AL.: "Antimicrobial activity of basic cholane derivatives part IX", ARCHIV DES PHARMAZIE, vol. 323, no. 4, pages 201 - 205, XP055024553, DOI: doi:10.1002/ardp.19903230404
S.M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI, vol. 66, 1977, pages l-19
WEN-HUA CHEN ET AL.: "A bioconjugate approach toward squalamine mimics: insight into the mechanism of the biological action", BIOCONJUGATE CHEMISTRY, vol. 17, no. 6, pages 1582 - 1591, XP055353519, DOI: doi:10.1021/bc060220n
WEN-HUA CHEN ET AL: "A Bioconjugate Approach toward Squalamine Mimics: Insight into the Mechanism of Biological Action", BIOCONJUGATE CHEMISTRY, vol. 17, no. 6, 1 November 2006 (2006-11-01), pages 1582 - 1591, XP055353519, ISSN: 1043-1802, DOI: 10.1021/bc060220n *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023208988A1 (en) * 2022-04-26 2023-11-02 Université D'aix-Marseille Antibacterial compounds eliminating dormant bacterial cells

Also Published As

Publication number Publication date
EP3512864B1 (en) 2021-01-20
CN109996804A (en) 2019-07-09
FR3055802B1 (en) 2018-08-24
FR3055802A1 (en) 2018-03-16
US10780101B2 (en) 2020-09-22
EP3512864A1 (en) 2019-07-24
CN109996804B (en) 2022-04-08
US20190262362A1 (en) 2019-08-29

Similar Documents

Publication Publication Date Title
EP3512865B1 (en) Esters of 3-polyamine derivatives of bile acids for the treatment of infections
TWI422372B (en) Rifamycin derivatives
RU2413513C2 (en) Anthelminthic composition of quaternary phosphonium salt and substituted dinitrobenzofuroxane
KR20140129030A (en) Compounds and methods for treating candidiasis and aspergillus infections
EP2124930A1 (en) Isosorbide mononitrate derivatives for the treatment of intestinal disorders
EP3512864B1 (en) Amide derivatives of squalamine for the treatment of infections
EP3268008B1 (en) Compounds that are analogs of squalamine, used as antibacterial agents
EP0974598A2 (en) New erythromycin derivatives, process for making them and their use as medicines
CA3111976A1 (en) Deuterated secnidazole for use in the treatment of bacterial vaginosis and methods and uses thereof
EP1030673B1 (en) Use of ketolides for preventing arterial thrombotic complications related to atherosclerosis
US6423707B1 (en) Nitroimidazole ester analogues and therapeutic applications
EP0946579B1 (en) Novel erythromycin derivatives, method for preparing them and their use as medicine
US8058468B2 (en) Carbamate antibiotics
US20170355671A1 (en) Peripherally substituted monocyclic beta-lactams
CA1140111A (en) PROCESS FOR PREPARING A NEW DERIVATIVE OF (20S) 3.alpha.-/(AMINO-ACETYL) AMINO/5.alpha.- PREGNAN-20-O1 AND THE SALTS THEREOF
FR2573071A1 (en) 2-[N-(2-Hydroxy-1,1-dimethylethyl)amino]-1-phenylethanol which is useful, in particular, as an anti-inflammatory, and process for preparing it
FR2588871A1 (en) NOVEL DERIVATIVES OF ACETIC THIOPHENE ACID, PROCESS FOR PREPARING THEM, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
JPS58118514A (en) Choleretic therapeutical composition containing cholanic acid derivative as active component
EP0161172A1 (en) N-(3-phenylmethylthio-1-oxo-propyl)-amino-acetic-acid derivatives, their preparation and their therapeutical use
JP2000034287A (en) Antimycotic agent
FR2533567A1 (en) 2-(ortho-Carboxyphenylamino)-6H-pyrimido[2,1-b]quinazol-6-one and its derivatives, process for preparing them and their therapeutic application
FR2602769A1 (en) NOVEL PHENOXY PROPYL DERIVATIVES AND THEIR SALTS, THE PREPARATION PROCESS, THE MEDICINAL APPLICATION OF THESE NEW PRODUCTS, AND THE COMPOSITIONS COMPRISING THE SAME
FR2468369A1 (en) MEDICAMENT COMPRISING A COMBINATION OF 3- (BETA-HYDROXY-ALPHA-METHYL-PHENETHYLAMINO) -3'-METHOXY-PROPIOPHENONE WITH THEOPHYLLIN OR THEOPHYLLINE DERIVATIVES

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17764847

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017764847

Country of ref document: EP

Effective date: 20190415